JP2011524894A - Nicotinamide derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I) as defined herein for substituents, pharmaceutically acceptable salts and solvates thereof, compositions containing such compounds, and allergic conditions and respiratory The use of such compounds for the treatment of conditions.
[Chemical 1]

Description

The present invention relates to nicotinamide derivatives, pharmaceutical compositions containing such derivatives, and their use as medicaments. More particularly, the present invention is a hematopoietic prostaglandin D ₂ synthase inhibitors are useful in the treatment of allergic conditions and diseases, as well as respiratory conditions and diseases, N- cycloalkyl-3-phenyl Nicotinamide derivatives are provided.

Prostaglandin D ₂ (PGD ₂ ) is a metabolite of arachidonic acid. PGD ₂ promotes sleep, suppresses platelet aggregation, relaxes smooth muscle contraction, induces bronchoconstriction, and attracts inflammatory cells including Th2 cells, eosinophils, and basophils. Both lipocalin-type PGD synthase (L-PGDS) and hematopoietic PGDS (H-PGDS) convert PGH ₂ to PGD ₂ .

L-PGDS, also known as glutathione-independent PGDS or brain-type PGDS, is a 26 kDa secreted protein expressed in the brain by meningeal cells, choroid plexus epithelial cells, and oligodendrocytes. L-PGDS secreted into the cerebrospinal fluid is thought to be a source of PGD ₂ in the central nervous system. In addition, epididymal cells of the epididymis and Leydig cells of the testis also express L-PGDS and are thought to be a source of PGD ₂ found in semen. L-PGDS belongs to the lipocalin superfamily consisting of lipophilic ligand carrier proteins such as retinol and retinoic acid binding protein.

In contrast, H-PGDS is a mast cell, antigen presenting cells, and cytoplasmic proteins of 26kDa responsible for synthesis of PGD ₂ in immune and inflammatory cells including Th2 cells. H-PGDS is the only vertebrate member of the sigma-type glutathione S transferase (GST). Both H-PGDS and L-PGDS convert PGH ₂ to PGD ₂ , but the catalytic mechanism and specific activity of these enzymes are quite different.

The production of PGD ₂ by H-PGDS is thought to play a pivotal role in the process of airway allergy and inflammation, and is responsible for vasodilation, bronchoconstriction, lung eosinophil and lymphocyte infiltration, and cytokine release in asthmatic patients. Trigger. PGD ₂ levels increase dramatically in bronchoalveolar lavage fluid after allergen challenge, and the findings that bronchoconstriction occurs when asthmatic patients inhale PGD ₂ indicate that pathological consequences of high levels of PGD ₂ in the lung Is emphasized. Treatment with PGD ₂ caused a significant nasal congestion and fluid secretion in humans and dogs, also PGD ₂ is 10 times more potent that histamine that cause nasal congestion in humans, is 100 times that of bradykinin, PGD ₂ in allergic rhinitis The role of has been demonstrated.

Several lines of evidence suggest that PGDS is an excellent target for allergies and respiratory diseases or conditions. Transgenic mice overexpressing H-PGDS show increased allergic reactivity with increased levels of Th2 cytokines and chemokines, and increased accumulation of eosinophils and lymphocytes in the lung. In addition, PGD ₂ binds to two GPCR receptors, DP1 and CRTH2. Airway and inflammatory responses induced by antigens, significantly decreased in DP1- receptor-deficient mice, new evidence that binding to CRTH2 of PGD _2, Th2 cells in vitro, eosinophils, and basophils Has been shown to mediate cell migration and activation, and possibly promote allergic diseases in vivo. Finally, in several published reports, polymorphisms in the H-PGDS gene are associated with atopic asthma. For example, Aritake et al., “Structural and Functional Charactrization of OF HQL-79, and Orly Selective Inhibitor of Humans, J. It provides a reasonable basis to consider it an effective means of treating several allergic and non-allergic diseases.

  There is a need to provide novel inhibitors of H-PDGS that are suitable as drug candidates. Such compounds must be potent selective inhibitors of H-PGDS with proper metabolic stability and pharmacokinetic properties. This time, compounds have been discovered that are inhibitors of H-PGDS and do not substantially inhibit L-PGDS or kinases at the expected effective dose.

  Accordingly, the present invention provides a compound of formula (I) as embodiment E1:

もしくは薬学的に許容できるその塩、または前記化合物もしくは塩の薬学的に許容できる溶媒和物を提供する。式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、それぞれ独立に、Ｈ、Ｆ、Ｃｌ、−ＣＮ、−ＮＨ_２、−ＣＨ_３、−ＣＨ_２Ｆ、−ＣＨＦ_２、−ＣＦ_３、−ＯＨ、−ＯＣＨ_３、−ＯＣＨ_２Ｆ、−ＯＣＨＦ_２、または−ＯＣＦ_３であり、
Ｒ^６は、Ｈ、−ＮＨ_２、−ＯＨ、または−ＣＨ_３であり、
Ｒ^６ａは、Ｈ、Ｆ、またはＣｌであり、
Ｒ^７は、Ｃ_１〜Ｃ_６アルキル、フェニル、Ｈｅｔ^１、Ｈｅｔ^２、Ｈｅｔ^３、またはＨｅｔ^４であり、前記Ｃ_１〜Ｃ_６アルキル、フェニル、Ｈｅｔ^１、Ｈｅｔ^２、Ｈｅｔ^３、またはＨｅｔ^４は、（ａ）Ｒ^ａ、−ＯＲ^ｂ、−Ｓ（Ｏ）_ｎＲ^ｂ、−ＣＯＲ^ｂ、−ＮＲ^ｘＲ^ｂ、−ＯＣＯＲ^ｂ、−ＣＯＯＲ^ｂ、−ＮＲ^ｘＣＯＲ^ｂ、−ＣＯＮＲ^ｘＲ^ｂ、−ＮＲ^ｘＳＯ_２Ｒ^ｂ、−ＳＯ_２ＮＲ^ｘＲ^ｂ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＲ^ｂ、−ＮＲ^ｘＣＯＯＲ^ｂ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｂ、−ＯＣＯＮＲ^ｘＲ^ｂ、−ＯＣＯＯＲ^ｂ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｂ、オキソ、および−ＣＮから選択される１〜３個の置換基で置換されていてもよく、さらに（ｂ）１個または複数のハロ原子で置換されていてもよく、
Ｒ^ａは、各場合において、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８はそれぞれ、Ｒ^ｃ、−ＯＲ^ｄ、−Ｓ（Ｏ）_ｎＲ^ｄ、−ＣＯＲ^ｄ、−ＮＲ^ｘＲ^ｄ、−ＯＣＯＲ^ｄ、−ＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＲ^ｄ、−ＣＯＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＳＯ_２Ｒ^ｄ、−ＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＯＲ^ｄ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｄ、オキソ、および−ＣＮから選択される１〜３個の置換基、ならびに１個または複数のハロ原子で置換されていてもよく、
Ｒ^ｂは、各場合において、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８はそれぞれ、Ｒ^ｃ、−ＯＲ^ｄ、−Ｓ（Ｏ）_ｎＲ^ｄ、−ＣＯＲ^ｄ、−ＮＲ^ｘＲ^ｄ、−ＯＣＯＲ^ｄ、−ＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＲ^ｄ、−ＣＯＮＲ^ｘＲ^ｄ −ＮＲ^ｘＳＯ_２Ｒ^ｄ、−ＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＯＲ^ｄ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｄ、オキソ、および−ＣＮから選択される１〜３個の置換基、ならびに１個または複数のハロ原子で置換されていてもよく、
ｎは、０、１または２であり、
Ｒ^ｘは、各場合において、それぞれ独立に、Ｈ、Ｃ_１〜Ｃ_６アルキル、またはＣ_３〜Ｃ_８シクロアルキルであり、前記Ｃ_１〜Ｃ_６アルキルまたはＣ_３〜Ｃ_８シクロアルキルは、１個または複数のハロ原子で置換されていてもよく、
Ａｒｙｌ^１は、フェニルまたはナフチルであり、
Ｈｅｔ^１は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、３〜８員の飽和または部分的不飽和の単環式複素環であり、但し、Ｈｅｔ^１は、ピペリジニル、ピロリジニルおよびアゼチジニルではなく、
Ｈｅｔ^２は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、６〜１２員の飽和または部分的不飽和の多環式複素環であり、但し、Ｈｅｔ^２は、架橋ピペリジニル、ピロリジニルまたはアゼチジニル環ではなく、
Ｈｅｔ^３は、（ｉ）１〜３個のＮ原子を含んでいる６員芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる５員芳香族複素環であり、
Ｈｅｔ^４は、（ｉ）１〜４個のＮ原子を含んでいる１０員二環式芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる９員二環式芳香族複素環であり、
Ｈｅｔ^５は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、３〜８員の飽和または部分的不飽和の単環式複素環であり、
Ｈｅｔ^６は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、６〜１２員の飽和または部分的不飽和の多環式複素環であり、
Ｈｅｔ^７は、（ｉ）１〜３個のＮ原子を含んでいる６員芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる５員芳香族複素環であり、
Ｈｅｔ^８は、（ｉ）１〜４個のＮ原子を含んでいる１０員二環式芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる９員二環式芳香族複素環であり、
Ｒ^ｃは、各場合において、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２はそれぞれ、Ｒ^ｅから選択される１〜３個の置換基および１個または複数のハロ原子で置換されていてもよく、
Ｒ^ｄは、各場合において、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２はそれぞれ、Ｒ^ｅから選択される１〜３個の置換基および１個または複数のハロ原子で置換されていてもよく、
Ａｒｙｌ^２は、フェニルまたはナフチルであり、
Ｈｅｔ^９は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる３〜８員の飽和または部分的不飽和の単環式複素環であり、
Ｈｅｔ^１０は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる６〜１２員の飽和または部分的不飽和の多環式複素環であり、
Ｈｅｔ^１１は、（ｉ）１〜３個のＮ原子を含んでいる６員芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる５員芳香族複素環であり、
Ｈｅｔ^１２は、（ｉ）１〜４個のＮ原子を含んでいる１０員二環式芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる９員二環式芳香族複素環であり、
Ｒ^ｅは、−ＯＲ^ｘ、−Ｓ（Ｏ）_ｎＲ^ｘ、−ＣＯＲ^ｘ、−ＮＲ^ｘＲ^ｘ、−ＯＣＯＲ^ｘ、−ＣＯＯＲ^ｘ、−ＮＲ^ｘＣＯＲ^ｘ、−ＣＯＮＲ^ｘＲ^ｘ、−ＮＲ^ｘＳＯ_２Ｒ^ｘ、−ＳＯ_２ＮＲ^ｘＲ^ｘ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＮＲ^ｘ、−ＮＲ^ｘＣＯＯＲ^ｘ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｘ、−ＯＣＯＮＲ^ｘＲ^ｘ、−ＯＣＯＯＲ^ｘ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｘ、オキソ、または−ＣＮであり、
但し、式（Ｉ）の化合物は、
２−ヒドロキシ−Ｎ，６−ジフェニル−３−ピリジンカルボキサミド、
Ｎ，６−ジフェニル−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−フェニル−３−ピリジンカルボキサミド、
６−（２−フルオロフェニル）−Ｎ−フェニル−３−ピリジンカルボキサミド、
６−（２−メチルフェニル）−Ｎ−フェニル−３−ピリジンカルボキサミド、
２−メチル−Ｎ，６−ジフェニル−３−ピリジンカルボキサミド、
Ｎ−（５−ブチル−１，３，４−チアジアゾール−２−イル）−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−（４−アセチル−２−チアゾリル）−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
５−［［（２−メチル−６−フェニル−３−ピリジニル）カルボニル］アミノ］−２−チオフェンカルボン酸、メチルエステル、
Ｎ−［４−（１，１−ジメチルエチル）−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［４−［５−［（アセチルアミノ）メチル］−２−チエニル］−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［４−［４−［（メチルスルホニル）（メチル）アミノ］フェニル］−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［４−［４−（アセチルアミノ）−２−フルオロフェニル］−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［４−［（２，６−ジメチル−４−モルホリニル）メチル］−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［５−［１−（ジフルオロメチル）−１Ｈ−イミダゾール−２−イル］−４−メチル−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［５−（１−エチルプロピル）−１，３，４−チアジアゾール−２−イル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−（３，５−ジメチル−１−フェニル−１Ｈ−ピラゾール−４−イル）−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−アンチピリニル−２−メチル−６−フェニル−ニコチンアミド、
１，２−ジヒドロ−２−オキソ−６−フェニル−Ｎ−１Ｈ−テトラゾール−５−イル−３−ピリジンカルボキサミド、
２−メチル−６−フェニル−Ｎ−２−チアゾリル−３−ピリジンカルボキサミド、
２−メチル−Ｎ−（５−メチル−２−チアゾリル）−６−フェニル−３−ピリジンカルボキサミド、
２−メチル−Ｎ−（４−メチル−２−ピリジニル）−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−（５−エチル−１，３，４−チアジアゾール−２−イル）−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［４−（２−アミノ−２−オキソエチル）−２−チアゾリル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド、または
Ｎ−［５−（エチルチオ）−１，３，４−チアジアゾール−２−イル］−２−メチル−６−フェニル−３−ピリジンカルボキサミド；
６−（２−メチルフェニル）−Ｎ−［２−［［［１−フェニル−３−（トリフルオロメチル）−１Ｈ−ピラゾール−４−イル］カルボニル］アミノ］エチル］−３−ピリジンカルボキサミド、
Ｎ−［２−（５−メトキシ−１Ｈ−インドール−３−イル）エチル］−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−［４−［４−［１−（２−アミノ−２−オキソエトキシ）−５，６，７，８−テトラヒドロ−２−ナフタレニル］−１−ピペリジニル］ブチル］−６−（４−クロロフェニル）−３−ピリジンカルボキサミド、
Ｎ−［４−［４−［１−（２−アミノ−２−オキソエトキシ）−５，６，７，８−テトラヒドロ−２−ナフタレニル］−１−ピペリジニル］ブチル］−６−（４−シアノフェニル）−３−ピリジンカルボキサミド、
６−（４−クロロフェニル）−Ｎ−［４−［４−（５，６，７，８−テトラヒドロ−１−メトキシ−２−ナフタレニル］−１−ピペリジニル］ブチル］−３−ピリジンカルボキサミド、
６−（４−クロロフェニル）−Ｎ−［４−［４−（５，６，７，８−テトラヒドロ−１−メトキシ−２−ナフタレニル］−１−ピペリジニル］ブチル］−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ）−２−［（シアノメチル）アミノ］−１−［（２，６−ジフルオロフェニル）メチル］−２−オキソエチル］−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ）−２−［（シアノメチル）アミノ］−１−［（２，６−ジフルオロ−４−メトキシフェニル）メチル］−２−オキソエチル］−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ）−２−［（４−シアノ−１−エチル−４−ピペリジニル）アミノ］−１−［（２，６−ジフルオロフェニル）メチル］−２−オキソエチル］−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ）−２−［（シアノメチル）アミノ］−２−オキソ−１−（２−チアゾリルメチル）エチル］−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ，３Ｓ）−１−［［（４−シアノ−１−エチル−４−ピペリジニル）アミノ］カルボニル］−３−フェニル）ブチル］−３−ピリジンカルボキサミド、
Ｎ−［［６−（２−クロロフェニル）−３−ピリジニル］カルボニル］−２，６−ジフルオロ−Ｌ−フェニルアラニン、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ）−２−［（シアノメチル）アミノ］−１−［（２，６−ジフルオロフェニル）メチル］−２−オキソエチル］−３−ピリジンカルボキサミド、
６−（２−クロロフェニル）−Ｎ−［（１Ｓ）−１−［［（シアノメチル）アミノ］カルボニル］−３−メチルブチル］−３−ピリジンカルボキサミド、
６−（４−メトキシフェニル）−Ｎ−［２−［４−（１−ピロリジニルメチル）フェニル］エチル］−３−ピリジンカルボキサミド、
６−（４−フルオロフェニル）−Ｎ−［２−［４−（１−ピロリジニルメチル）フェニル］エチル］−３−ピリジンカルボキサミド、
α−［［［６−（３，４−ジメトキシフェニル）−１，２−ジヒドロ−２−オキソ−３−ピリジニル］カルボニル］アミノ］−４−ヒドロキシ−ベンゼン酢酸、
Ｎ−［４−［４−（２，４−ジメトキシフェニル）−１−ピペラジニル］ブチル］−６−フェニル−３−ピリジンカルボキサミド、
５−［［２−（４−フルオロフェニル）−１，１−ジメチルエチルアミノ］−４−［［［６−（３−メトキシフェニル）−３−ピリジニル］カルボニル］アミノ］−５−オキソ−ペンタン酸、
５−［［２−（４−フルオロフェニル）−１，１−ジメチルエチルアミノ］−５−オキサ−４−［［（６−フェニル）−３−ピリジニル］カルボニル］アミノ］−（４Ｓ）−ペンタン酸、
５−［（１，１−ジメチル−２−フェニルエチル）アミノ］−５−オキソ−４−［［（６−フェニル）−３−ピリジニル］カルボニル］アミノ］−ペンタン酸、
５−［［２−（４−クロロフェニル）−１，１−ジメチルエチル］アミノ］−５−オキソ−４−［［（６−フェニル−３−ピリジニル）カルボニル］アミノ］−（４Ｓ）−ペンタン酸、
５−オキソ−５−［（フェニルメチル）アミノ］−４−［［（６−フェニル−３−ピリジニル）カルボニル］アミノ］−（４Ｓ）−ペンタン酸１，１−ジメチルエチルエステル、
５−オキソ−５−［（フェニルメチル）アミノ］−４−［［（６−フェニル−３−ピリジニル）カルボニル］アミノ］−ペンタン酸、
５−［［（３−メトキシフェニル）メチル］アミノ］−５−オキソ−４−［［（６−フェニル−３−ピリジニル）カルボニル］アミノ］−（４Ｓ）−ペンタン酸１，１−ジメチルエチルエステル、
５−［［（３−メトキシフェニル）メチル］アミノ］−５−オキソ−４−［［（６−フェニル−３−ピリジニル）カルボニル］アミノ］−（４Ｓ）−ペンタン酸、
Ｎ−（２−フラニルメチル）−２−メチル−６−フェニル−３−ピリジンカルボキサミド、
Ｎ−メチル−６−フェニル−３−ピリジンカルボキサミド、または
６−（４−メトキシフェニル）−Ｎ−［［３−［（８−メチル−８−アザビシクロ［３．２．１］オクト−３−イル）フェニル］メチル］−３−ピリジンカルボキサミドではなく、
またＲ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５がそれぞれＨであり、Ｒ^７が、置換されていてもよいＣ_１〜Ｃ_６アルキルであるとき、Ｒ^６は、ＣＨ_３またはＯＨではなく、
またＲ^１、Ｒ^２、Ｒ^４およびＲ^５がそれぞれＨであり、Ｒ^３がトリフルオロメチルであり、Ｒ^６がＣＨ_３であり、Ｒ^７が、Ｒ^ａで置換されているメチルまたはエチルであるとき、Ｒ^ａは、置換されていてもよいフェニル環または置換されていてもよいフェノキシ基ではなく、
またＲ^１、Ｒ^２、Ｒ^４およびＲ^５がそれぞれＨであり、Ｒ^３がＦであり、Ｒ^６がＨであり、Ｒ^７が、Ｒ^ａで置換されているメチルであるとき、Ｒ^ａは、置換されていてもよいキノリニル基ではなく、
またＲ^１およびＲ^５の一方がＣｌであり、Ｒ^１およびＲ^５の他方がＨであり、Ｒ^２がＨであり、Ｒ^３がＨであり、Ｒ^４がＨであり、Ｒ^７が、−ＣＯＮＲ^ｘＲ^ｂで置換されているメチルであり、Ｒ^ｂがプロピルであるとき、Ｒ^ｂは、−ＣＯＨｅｔ^３または−ＣＯＨｅｔ^４で置換されておらず、
またＲ^６がＨであり、Ｒ^６ａがＨであり、Ｒ^７が、Ｒ^ａで置換されているメチルであるとき、Ｒ^ａは、置換されているフェニル基ではなく、
またＲ^６がＨであり、Ｒ^６ａがＨであるとき、Ｒ^７は、（ＣＨ_３）_２ＣＨＣＨ_２ＣＨ_２−ではない。

Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. Where
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, —CN, —NH ₂ , —CH ₃ , —CH ₂ F, —CHF ₂ , —CF ₃ , _-OH, -OCH _3, a -OCH ₂ F, -OCHF 2 or -OCF _3,,
R ⁶ is H, —NH ₂ , —OH, or —CH ₃ ;
R ^6a is H, F, or Cl;
R ⁷ is C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ , said C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ Are: (a) R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , —CONR ^x R ^{b _{, -NR x SO 2 R b,}} -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R b, -OCOOR b , -CONR ^x SO ₂ R ^b, oxo, and -CN may be substituted with 1-3 substituents selected from, optionally substituted with further (b) 1 one or more halo atoms Often,
R ^a is independently from each other C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ^{8 in} each case. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ⁸ are R ^c , —OR, respectively. _{^{d, -S (O) n R}} d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d, -NR x SO 2 R d, - _{^{SO 2 NR x R d, -NR}} x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR d -CONR ^x SO ₂ R ^d, oxo, and one to three substituents selected from -CN, and may be substituted with one or more halo atoms,
R ^b is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ and Het ⁸ respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 1, Het 5, Het} 6, Het 7, and Het ^{8 each, R} c, _{^{-OR d, -S (O) n}} R d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d -NR x SO 2 R d, _{^{-SO 2 NR x R d, -NR}} x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR , -CONR ^x SO ₂ R ^d, oxo, and one to three substituents selected from -CN, and may be substituted with one or more halo atoms,
n is 0, 1 or 2;
R ^x is, independently in each case, H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl is 1 Optionally substituted with one or more halo atoms,
Aryl ¹ is phenyl or naphthyl;
Het ¹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ¹ is piperidinyl , Not pyrrolidinyl and azetidinyl
Het ² is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ² is a bridged Not a piperidinyl, pyrrolidinyl or azetidinyl ring,
Het ³ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁴ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
Het ⁵ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁶ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁷ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁸ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^c is independently in each case from C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ^12. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² are each selected from R ^e Optionally substituted with 1 to 3 substituents and one or more halo atoms,
R ^d is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 2, Het 9, Het} 10, Het 11, and ^{Het 12} each, from ^{R e} Optionally substituted with 1 to 3 selected substituents and one or more halo atoms,
Aryl ² is phenyl or naphthyl;
Het ⁹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹⁰ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹¹ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ¹² may be (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^{e _{is, -OR x, -S (O)}} n R x, -COR x, -NR x R x, -OCOR x, -COOR x, -NR x COR x, -CONR x R x, -NR x _{^{SO 2 R x, -SO 2 NR}} x R x, -NR x SO 2 NR x NR x, -NR x COOR x, -NR x CONR x R x, -OCONR x R x, -OCOOR x, -CONR x SO ₂ R ^x , oxo, or —CN,
Provided that the compound of formula (I) is
2-hydroxy-N, 6-diphenyl-3-pyridinecarboxamide,
N, 6-diphenyl-3-pyridinecarboxamide,
6- (2-chlorophenyl) -N-phenyl-3-pyridinecarboxamide,
6- (2-fluorophenyl) -N-phenyl-3-pyridinecarboxamide,
6- (2-methylphenyl) -N-phenyl-3-pyridinecarboxamide,
2-methyl-N, 6-diphenyl-3-pyridinecarboxamide,
N- (5-butyl-1,3,4-thiadiazol-2-yl) -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- (4-acetyl-2-thiazolyl) -2-methyl-6-phenyl-3-pyridinecarboxamide,
5-[[(2-methyl-6-phenyl-3-pyridinyl) carbonyl] amino] -2-thiophenecarboxylic acid, methyl ester,
N- [4- (1,1-dimethylethyl) -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- [5-[(acetylamino) methyl] -2-thienyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- [4-[(methylsulfonyl) (methyl) amino] phenyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- [4- (acetylamino) -2-fluorophenyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4-[(2,6-dimethyl-4-morpholinyl) methyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [5- [1- (difluoromethyl) -1H-imidazol-2-yl] -4-methyl-2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [5- (1-ethylpropyl) -1,3,4-thiadiazol-2-yl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -2-methyl-6-phenyl-3-pyridinecarboxamide;
N-antipyridyl-2-methyl-6-phenyl-nicotinamide,
1,2-dihydro-2-oxo-6-phenyl-N-1H-tetrazol-5-yl-3-pyridinecarboxamide,
2-methyl-6-phenyl-N-2-thiazolyl-3-pyridinecarboxamide,
2-methyl-N- (5-methyl-2-thiazolyl) -6-phenyl-3-pyridinecarboxamide,
2-methyl-N- (4-methyl-2-pyridinyl) -6-phenyl-3-pyridinecarboxamide,
N- (5-ethyl-1,3,4-thiadiazol-2-yl) -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- (2-amino-2-oxoethyl) -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide or N- [5- (ethylthio) -1,3,4-thiadiazole -2-yl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
6- (2-methylphenyl) -N- [2-[[[1-phenyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] carbonyl] amino] ethyl] -3-pyridinecarboxamide;
N- [2- (5-methoxy-1H-indol-3-yl) ethyl] -6-phenyl-3-pyridinecarboxamide;
N- [4- [4- [1- (2-Amino-2-oxoethoxy) -5,6,7,8-tetrahydro-2-naphthalenyl] -1-piperidinyl] butyl] -6- (4-chlorophenyl ) -3-pyridinecarboxamide,
N- [4- [4- [1- (2-Amino-2-oxoethoxy) -5,6,7,8-tetrahydro-2-naphthalenyl] -1-piperidinyl] butyl] -6- (4-cyano Phenyl) -3-pyridinecarboxamide,
6- (4-chlorophenyl) -N- [4- [4- (5,6,7,8-tetrahydro-1-methoxy-2-naphthalenyl] -1-piperidinyl] butyl] -3-pyridinecarboxamide;
6- (4-chlorophenyl) -N- [4- [4- (5,6,7,8-tetrahydro-1-methoxy-2-naphthalenyl] -1-piperidinyl] butyl] -3-pyridinecarboxamide;
6- (2-chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -1-[(2,6-difluorophenyl) methyl] -2-oxoethyl] -3-pyridinecarboxamide;
6- (2-Chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -1-[(2,6-difluoro-4-methoxyphenyl) methyl] -2-oxoethyl] -3-pyridine Carboxamide,
6- (2-Chlorophenyl) -N-[(1S) -2-[(4-cyano-1-ethyl-4-piperidinyl) amino] -1-[(2,6-difluorophenyl) methyl] -2- Oxoethyl] -3-pyridinecarboxamide,
6- (2-chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -2-oxo-1- (2-thiazolylmethyl) ethyl] -3-pyridinecarboxamide;
6- (2-Chlorophenyl) -N-[(1S, 3S) -1-[[(4-cyano-1-ethyl-4-piperidinyl) amino] carbonyl] -3-phenyl) butyl] -3-pyridinecarboxamide ,
N-[[6- (2-chlorophenyl) -3-pyridinyl] carbonyl] -2,6-difluoro-L-phenylalanine,
6- (2-chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -1-[(2,6-difluorophenyl) methyl] -2-oxoethyl] -3-pyridinecarboxamide;
6- (2-chlorophenyl) -N-[(1S) -1-[[(cyanomethyl) amino] carbonyl] -3-methylbutyl] -3-pyridinecarboxamide;
6- (4-methoxyphenyl) -N- [2- [4- (1-pyrrolidinylmethyl) phenyl] ethyl] -3-pyridinecarboxamide;
6- (4-fluorophenyl) -N- [2- [4- (1-pyrrolidinylmethyl) phenyl] ethyl] -3-pyridinecarboxamide;
α-[[[[6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxo-3-pyridinyl] carbonyl] amino] -4-hydroxy-benzeneacetic acid,
N- [4- [4- (2,4-dimethoxyphenyl) -1-piperazinyl] butyl] -6-phenyl-3-pyridinecarboxamide;
5-[[2- (4-Fluorophenyl) -1,1-dimethylethylamino] -4-[[[[6- (3-methoxyphenyl) -3-pyridinyl] carbonyl] amino] -5-oxo-pentane acid,
5-[[2- (4-Fluorophenyl) -1,1-dimethylethylamino] -5-oxa-4-[[(6-phenyl) -3-pyridinyl] carbonyl] amino]-(4S) -pentane acid,
5-[(1,1-dimethyl-2-phenylethyl) amino] -5-oxo-4-[[(6-phenyl) -3-pyridinyl] carbonyl] amino] -pentanoic acid,
5-[[2- (4-Chlorophenyl) -1,1-dimethylethyl] amino] -5-oxo-4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid ,
5-oxo-5-[(phenylmethyl) amino] -4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid 1,1-dimethylethyl ester;
5-oxo-5-[(phenylmethyl) amino] -4-[[(6-phenyl-3-pyridinyl) carbonyl] amino] -pentanoic acid,
5-[[(3-Methoxyphenyl) methyl] amino] -5-oxo-4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid 1,1-dimethylethyl ester ,
5-[[(3-methoxyphenyl) methyl] amino] -5-oxo-4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid,
N- (2-furanylmethyl) -2-methyl-6-phenyl-3-pyridinecarboxamide,
N-methyl-6-phenyl-3-pyridinecarboxamide, or 6- (4-methoxyphenyl) -N-[[3-[(8-methyl-8-azabicyclo [3.2.1] oct-3-yl ) Not phenyl] methyl] -3-pyridinecarboxamide,
When R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each H and R ⁷ is an optionally substituted C ₁ -C ₆ alkyl, R ⁶ is CH ₃ or OH. Not
R ¹ , R ² , R ⁴ and R ⁵ are each H, R ³ is trifluoromethyl, R ⁶ is CH ₃ , and R ⁷ is methyl or ethyl substituted with ^Ra In certain instances, R ^a is not an optionally substituted phenyl ring or an optionally substituted phenoxy group,
Also an ^{R 1,} R 2, ^{R 4} and ^{R 5} are each H, ^{R 3} is F, and ^{R 6} is H, when ^{R 7} is methyl substituted with ^{R a, R a} Is not an optionally substituted quinolinyl group,
And ^one of R ¹ and R ⁵ is Cl, the other of R ¹ and R ⁵ is H, R ² is H, R ³ is H, R ⁴ is H, R ⁷ is When methyl substituted with -CONR ^x R ^b and R ^b is propyl, R ^b is not substituted with -COHet ³ or -COHet ⁴ ;
The ^{R 6} is ^{H, R 6a} is H, ^{R 7} is, when it is methyl substituted with ^{R a, R a} is not a phenyl group which is substituted,
When R ⁶ is H and R ^6a is H, R ⁷ is not (CH ₃ ) ₂ CHCH ₂ CH ₂ —.

In preferred embodiment E2, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, —CH ₃ , —OH or —OCH ₃ , and R ⁶ , R ^6a and R 5 ⁷ is as defined in the above embodiment E1.

In a preferred embodiment E3, R ¹ is H and R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, —CH ₃ , —OH or OCH ₃ and R ⁶ , R ^6a and R ⁷ are as defined in embodiment E1 above.

In a preferred embodiment E4, R ¹ , R ³ , R ⁴ and R ⁵ are H, R ² is F, or R ¹ , R ³ , R ⁴ and R ⁵ are H and R ² is —CH ₃ Or R ¹ , R ³ , R ⁴ and R ⁵ are H, R ² is —OCH ₃ , or R ¹ , R ² , R ⁴ and R ⁵ are H, R ³ is F, or R ¹ , R ³ and R ⁵ are H, R ² and R ⁴ are both F, or R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each H, or R ¹ , R ³ and R ⁵ is H, R ² is F, R ⁴ is —OCH ₃ , or R ¹ , R ³ and R ⁴ are H, R ² is F, R ⁵ is —OH, R ⁶ , R ^6a and R ⁷ is as defined in the above embodiment E1.

In preferred embodiment E5, R ¹ , R ³ , R ⁴ and R ⁵ are H, R ² is F, and R ⁶ , R ^6a and R ⁷ are as defined in embodiment E1 above.

In a preferred embodiment E6, R ⁶ is H and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a and R ⁷ are as defined in embodiment E1 above.

In preferred embodiment E7, R ^6a is H or Cl, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in embodiment E1 above.

In preferred embodiment E8, R ^6a is H and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in embodiment E1 above.

In a preferred embodiment E9, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents chosen from -CN, be further substituted with one or more halo atoms C ₁ -C ₆ alkyl, which may be R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a , as defined in embodiment E1 above.

In preferred embodiment E9a, R ⁷ is C ₁ -C ₆ alkyl and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above. is there.

In a preferred embodiment ^{E9b, R} 7 _{is, -OH, -N (C 1 ~C} 6 _{alkyl) (C} 1 _{~C 6 alkyl), - O (C 1 ~C} 6 _alkyl), - CO 2 _H, -NH - _(C 1 ~C ₆ alkylene) -O _(C 1 _{~C 6 alkyl), - COO (C 1 ~C} 6 _{alkyl), - CN, -SO 2 (} C 1 ~C 6 alkyl), - CON (C ₁ -C _{6 alkyl) (C} 1 ~C _{6 alkyl), - CONH- (C 1 ~C} 6 alkylene) -COO _(C 1 ~C _{6 alkyl), - O- (C 1 ~C} 6 alkylene) -OH _{, -NH 2, -NHCOO- (C 1} ~C 6 alkylene) - phenyl, substituted with -CO _(C 1 ~C ₆ alkyl), and _C 1 -C ₆ 1 to 3 substituents selected from alkyl C ₁ -C ₆ alkyl, which may be R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E9c, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms And R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiments E9d, R ⁷ is phenyl, —CN, —OH, —COO (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, —COO— (C ₁ -C ₆ alkylene) -phenyl. , Methyl optionally substituted with 1 to 3 substituents selected from Het ⁵ , Het ⁶ , Het ⁷ , and Het ⁸ , said phenyl, C ₃ -C ₈ cycloalkyl, Het ⁵ , Het ⁶ , Het ⁷ , and Het ⁸ are C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl-CO (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkoxy, (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, _halo, C 1 -C ₆ haloalkyl, -S _(C 1 ~C _{6 alkyl), - SO 2 NH 2,} -COO (C 1 ~C 6 alkyl), _- SO 2 _{(C 1} C ₆ alkyl), phenyl, phenyl _(C 1 -C _{6 alkyl), (C} 1 -C ₆ alkoxy) phenyl, _((C 1 _{~C 6} alkoxy) _phenyl) C 1 -C ₆ alkyl, - _(C 1 ~ C ₆ alkylene) -SO _2- (C ₁ -C ₆ alkyl), halophenyl, Het ⁹ , Het ¹⁰ , Het ¹¹ , -COHet ⁹ ,-(C ₁ -C ₆ alkylene) -Het ⁹ ,-(C _1- C _{6 ^{alkylene) -Het 11, -SO 2 NH (}} C 1 ~C 6 alkyl), - _(C 1 -C ₆ alkylene) -COO _(C 1 ~C ₆ alkyl), - are selected OH, and oxo may be substituted with 1-3 substituents, wherein ^Het 9, ^{Het 10,} and ^{Het 11} _are, C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 1 -C ₆ C _Alkyl, C 1 -C ₆ alkoxy _(C 1 -C ₆ alkyl), - OH, and with 1 to 3 substituents selected from oxo may be substituted.

In preferred embodiments E9e, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiments E9f, R ⁷ is phenyl, Het ⁵ , Het ⁷ , Het ⁸ , —NHHet ⁷ , —NHHet ⁸ , —O— (C ₁ -C ₆ alkylene) -Het ⁸ , —CN, —OH, _{-CONH 2, -CONH- (C 1 ~C} 6 _{^{alkylene) -Het 5, -COO (C 1}} ~C 6 _alkyl), C 3 _{~C 8} cycloalkyl, -NH (phenyl), - N _(C 1 ~ C _{6 alkyl) (C} 1 -C ₆ alkyl), - O (phenyl), and -NHCOO- _(C 1 ~C ₆ alkylene) - substituted with 1-3 substituents selected from phenyl a good ethyl, the ^phenyl, Het 5, Het ^7, and Het ⁸ are, -OH, _halo, C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl C ₃ -C ₈ cycloalkyl alkyl, C -C ₆ alkoxy, hydroxy _(C 1 -C ₆ alkyl), oxo, phenyl, _{halophenyl, (C} 1 -C ₆ alkyl) phenyl, phenyl _(C 1 -C ₆ alkyl), _{(hydroxyphenyl)} C 1 -C ₆ Alkyl, (C ₁ -C ₆ alkoxy) phenyl, Het ¹¹ ,-(C ₁ -C ₆ alkylene) -Het ⁹ , (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, and-(C ₁ -C _6- alkylene) -Het ¹¹ may be substituted with 1 to 3 substituents, wherein Het ⁹ and Het ¹¹ are C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy (C _1- C ₆ alkyl), and optionally substituted by 1 to 3 substituents selected from oxo.

In preferred embodiment E9g, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiments E9h, R ⁷ is Het ⁵ , Het ⁷ , Het ⁸ , —NHHet ⁷ , —NH ₂ , C ₃ -C ₈ cycloalkyl, —OH, oxo, —O (phenyl), and —O—. (C ₁ -C ₆ alkylene) -propyl which may be substituted with 1 to 3 substituents selected from phenyl, and said phenyl, Het ⁵ , Het ⁷ and Het ⁸ are C ₁ -C It may be substituted with 1 to 3 substituents selected from ₆ alkyl, C ₁ -C ₆ alkoxy, and oxo.

In preferred embodiments E9i, R ⁷ is phenyl, —CN, —OH, —NH ₂ , oxo, —COO (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, —COO— (C ₁ — C ₆ ^{alkylene) -NHHet 7, -NHHet 8, -O-} (C 1 ~C 6 _{^{alkylene) -Het 8, -O- (C 1}} ~C 6 alkylene) - _phenyl, -CONH _2, -CONH- (C ₁ -C ₆ ^alkylene) -Het 9, -NH (phenyl), phenyl, -N _(C 1 ~C _{6 alkyl) (C} 1 -C ₆ alkyl), - O (phenyl), - NHCOO- _(C 1 ~ C ₆ alkylene) - ^{phenyl, Het 5, Het 6, Het} 7, and optionally substituted with 1 to 3 substituents selected from Het ⁸ is optionally _C 1 -C ₃ alkyl, said phenyl C ₃ -C ₈ ^{cycloalkyl, Het 5, Het 6, Het} 7, and Het ⁸ _is, C 1 -C _{6 alkyl,} C 3 -C ₈ cycloalkyl -CO _(C 1 ~C _{6 alkyl), C} 1 ~ C ₆ alkoxy, (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, hydroxy (C ₁ -C ₆ alkyl), hydroxyphenyl (C ₁ -C ₆ alkyl), halophenyl, (C ₁ -C ₆ alkyl) phenyl, _halo, C 1 -C ₆ haloalkyl, -S _(C 1 ~C _{6 alkyl), - SO 2 NH 2,} -COO (C 1 ~C 6 _{alkyl), - SO 2 (C 1} ~C 6 alkyl) , phenyl, phenyl _(C 1 -C _{6 alkyl), (C} 1 -C ₆ alkoxyphenyl), _((C 1 ~C ₆ alkoxy) _phenyl) C 1 -C ₆ alkyl, - _(C 1 -C _Alkylene) -SO _{2 (C} 1 _{~C 6} alkyl), ^{halophenyl, Het 9, Het 10, Het} 11, -COHet 9, - (C 1 ~C 6 _{^{alkylene) -Het 9, - (C 1}} ~C 6 alkylene ) -Het ¹¹ , —SO ₂ NH (C ₁ -C ₆ alkyl), — (C ₁ -C ₆ alkylene) —COO (C ₁ -C ₆ alkyl), —OH, and 1-3 selected from oxo The Het ⁹ , Het ¹⁰ and Het ¹¹ may be substituted with C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. It may be substituted with 1 to 3 substituents selected from ₆ alkoxy (C ₁ -C ₆ alkyl), —OH, and oxo.

In a preferred embodiment E10, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms And R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiment E10a, R ⁷ may be substituted with one to two substituents selected from R ^a and —OR ^b, and may be further substituted with one or more halo atoms. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiment E10b, R ⁷ is phenyl optionally substituted with 1-3 substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and halo, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E11, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms Which may be Het ¹ and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiments E11a, R ⁷ is a 5 or 6 membered saturated heterocycle containing 1 O or N atom, wherein the heterocycle is R ^a , —OR ^b , —S (O) _n R ^{b, -COR b, -NR x R} b, -OCOR b, -COOR b, -NR x COR b, -CONR x R b, -NR x SO 2 R b, -SO 2 NR x R b, -NR _{^{x SO 2 NR x R b,}} -NR x COOR b, -NR x CONR x R b, -OCONR x R b, -OCOOR b, -CONR x SO 2 R b, 1 selected oxo, and -CN ^May be substituted with ˜3 substituents, may be further substituted with one or more halo atoms, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a Is defined in Embodiment E1 above. A cage.

In a preferred embodiment E11b, R ⁷ is a 5- or 6-membered saturated heterocycle containing 1 O or N atom, wherein the heterocycle is R ^a , —OR ^b , —COOR ^b , oxo, — R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a may be substituted with 1 to 3 substituents selected from NR ^x R ^b in the above embodiment E1 As specified.

In preferred embodiments E11c, R ⁷ is tetrahydropyranyl, pyrrolidinyl, azepinyl, or tetrahydrofuranyl, each selected from R ^a , —OR ^b , —COOR ^b , —COR ^b , oxo, —NR ^x R ^b Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiments E11d, R ⁷ is tetrahydropyranyl, pyrrolidinyl, azepinyl, or tetrahydrofuranyl, respectively, C ₁ -C ₆ alkyl, —OH, —COO (C ₁ -C ₆ alkyl), —CO ( C ₁ -C ₆ alkyl), Het ⁶ , Het ⁷ , Het ⁸ , Oxo, —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), — (C ₁ -C ₆ alkyl) Aryl ¹ Optionally substituted with 1 to 3 selected substituents, wherein said Het ⁶ , Het ⁷ , Het ⁸ , and Aryl ¹ are selected from C ₁ -C ₆ alkyl, —CN, and halo ^May be substituted with ˜3 substituents, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E12, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms And may be Het ² and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In preferred embodiment E12a, R ⁷ is Het ² optionally substituted with 1 to 3 substituents selected from R ^a , —COOR ^b , —SO ₂ R ^b , —COR ^b , and oxo. Yes, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E12b, R ⁷ is 1 oxygen atom, 1 nitrogen atom, or an 8-11 membered saturated or partially unsaturated complex containing 1 oxygen and 1 nitrogen atom. And the heterocyclic ring may be substituted with 1 to 3 substituents selected from R ^a , —COOR ^b , —SO ₂ R ^b , —COR ^b , and oxo, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E12c, R ⁷ is 1 oxygen atom, 1 nitrogen atom, or an 8-11 membered saturated or partially unsaturated complex containing 1 oxygen and 1 nitrogen atom. a ring, the heterocyclic _ring, C 1 -C ₆ alkyl, -COO _(C 1 ~C _{6 alkyl), - SO 2 (C 1} ~C 6 _{alkyl), - CO (C 1 ~C} 6 alkyl), Substituted with 1-3 substituents selected from Het ⁷ , Het ⁸ ,-(C ₁ -C ₆ alkylene) -Het ⁷ , (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, and oxo Het ⁷ and Het ⁸ may be substituted with a C ₁ -C ₆ alkyl, hydroxy (C ₁ -C ₆ alkyl), or morpholinylcarbonyl group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ And R ^6a are as defined in Embodiment E1 above.

In preferred embodiments E12d, R ⁷ is 8-azabicyclo [3.2.1] octyl, 3,4-dihydro-2H-chromenyl, azabicyclo [3.1.0] hex-6-yl], or 1- Oxa-8-azaspiro [4.5] decyl, C ₁ -C ₆ alkyl, —COO (C ₁ -C ₆ alkyl), —SO ₂ (C ₁ -C ₆ alkyl), —CO (C, respectively. ₁ -C ₆ ^{alkyl), Het 7, Het 8,} - (C 1 ~C 6 ^alkylene) -Het _7, 1 to 3 is selected _(C 1 -C _{6 alkoxy)} C 1 -C ₆ alkyl, and oxo may be substituted with substituents,, Het ⁷ and Het ⁸ _may C 1 -C ₆ alkyl, hydroxy _(C 1 -C ₆ alkyl), or optionally substituted by Mori morpholinyl group ^{R 1, R 2, R 3} , R 4, R 5, R 6 and ^{R 6a} are as defined above embodiment E1.

In a preferred embodiment E12e, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms And may be 8-azabicyclo [3.2.1] octyl (preferably 8-azabicyclo [3.2.1] oct-3-yl), R ¹ , R ² , R ³ , R ⁴ , R ^5. , ^{R 6} and ^{R 6a} is It is as defined above embodiment E1.

In preferred embodiments E12f, R ⁷ is C ₁ -C ₆ alkyl, —COO (C ₁ -C ₆ alkyl), —SO ₂ (C ₁ -C ₆ alkyl), —CO (C ₁ -C ₆ alkyl). Substituted with 1 to 3 substituents selected from: Het ⁷ , Het ⁸ ,-(C ₁ -C ₆ alkylene) -Het ⁷ , (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, and oxo 8-azabicyclo [3.2.1] octyl (preferably 8-azabicyclo [3.2.1] oct-3-yl), and Het ⁷ and Het ⁸ are C ₁ -C _6. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a may be substituted with alkyl, hydroxy (C ₁ -C ₆ alkyl), or morpholinylcarbonyl group. Specified in form E1 It is as.

In a preferred embodiment E13, R ⁷ is R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , _{^{-CONR x R b, -NR x SO}} 2 R b, -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R ^{b, -OCOOR b, -CONR x SO} 2 R b, oxo, and may be substituted with 1-3 substituents selected from -CN, be further substituted with one or more halo atoms And may be Het ³ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E13a, R ⁷ is Het ³ optionally substituted with 1 to 3 substituents R ^a and further substituted with one or more halo atoms, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E13b, R ⁷ is pyridyl or pyrid-2-oneyl optionally substituted with 1 to 3 substituents R ^a and further substituted with one or more halo atoms. Yes, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

In a preferred embodiment E13C, ^{R 7} is one of _C 1 -C ₆ pyridyl or pyrid-2-onyl optionally substituted with an alkyl group, the _C 1 -C ₆ alkyl group, with ^{R c} It may be substituted and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^6a are as defined in embodiment E1 above.

  In a preferred embodiment E14, the compound of formula (I) is a compound of formula (Ia):

もしくは薬学的に許容できるその塩、または前記化合物もしくは塩の薬学的に許容できる溶媒和物であり、Ｒ^７は、実施形態Ｅ１、Ｅ９、Ｅ９ａ、Ｅ９ｂ、Ｅ９ｃ、Ｅ９ｄ、Ｅ９ｅ、Ｅ９ｆ、Ｅ９ｇ、Ｅ９ｈ、Ｅ９ｉ、Ｅ１０、Ｅ１０ａ、Ｅ１０ｂ、Ｅ１１、Ｅ１１ａ、Ｅ１１ｂ、Ｅ１１ｃ、Ｅ１１ｄ、Ｅ１２、Ｅ１２ａ、Ｅ１２ｂ、Ｅ１２ｃ、Ｅ１２ｄ、Ｅ１２ｅ、Ｅ１２ｆ、Ｅ１３、Ｅ１３ａ、Ｅ１３ｂまたはＥ１３ｃのいずれか１つにおいて上で規定したとおりである。

Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, wherein R ⁷ is an embodiment E1, E9, E9a, E9b, E9c, E9d, E9e, E9f, E9g, Defined above in any one of E9h, E9i, E10, E10a, E10b, E11, E11a, E11b, E11c, E11d, E12, E12a, E12b, E12c, E12d, E12e, E12f, E13, E13a, E13b or E13c Just as you did.

Further preferred embodiments of the present invention include the definition shown in any one of embodiments E1, E2, E3, E4 or E5 for R ¹ -R ⁵ and the definition shown in embodiment E1 or E6 for R ⁶ , definition shown in any one of embodiments E1, E7 or E8 for R ^6a, and the ^{R 7} embodiment E1, E9, E9a, E9b, E9c, E9d, E9e, E9f, E9g, E9h, E9i, E10, E10a, E10b, E11, E11a, E11b, E11c, E11d, E12, E12a, E12b, E12c, E12d, E12e, E12f, E13, E13a, E13b or E13c are devised in combination with the definition shown in any one The

The present invention, in a subject in its need of treatment, a method of treating a disease or condition at least partially mediated by prostaglandin D ₂ generated by the H-PGDS, to the subject a therapeutically effective A method comprising administering an amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; a disease mediated at least in part by prostaglandin D ₂ produced by H-PGDS, or Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a condition; a compound of formula (I) for use as a medicament or a pharmaceutically acceptable a salt or solvate thereof; disease at least partially mediated by prostaglandin D ₂ generated by the H-PGDS also A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of a condition; a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical compositions comprising a acceptable excipients; H-PGDS for treating a disease or condition at least partially mediated by prostaglandin D ₂ generated by, compound or pharmaceutical of formula (I) Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable salt or solvate thereof.

  Note that in embodiment E1 defined above, some compounds and groups of compounds have been abandoned as they are already known per se. However, such compounds are not known with respect to the methods and uses described above, and therefore disclaimer can be excluded when claiming the invention for the use of such compounds. For example, the invention provides a method of treating a disease or condition mediated at least in part by prostaglandin D2 produced by H-PGDS in a subject in need thereof, wherein the subject is treated An effective amount of a compound of formula (I):

もしくは薬学的に許容できるその塩、または前記化合物もしくは塩の薬学的に許容できる溶媒和物を投与することを含む方法を、実施形態Ｅ１ａとして提供する。
式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、それぞれ独立に、Ｈ、Ｆ、Ｃｌ、−ＣＮ、−ＮＨ_２、−ＣＨ_３、−ＣＨ_２Ｆ、−ＣＨＦ_２、−ＣＦ_３、−ＯＨ、−ＯＣＨ_３、−ＯＣＨ_２Ｆ、−ＯＣＨＦ_２、または−ＯＣＦ_３であり、
Ｒ^６は、Ｈ、−ＮＨ_２、−ＯＨ、または−ＣＨ_３であり、
Ｒ^６ａは、Ｈ、Ｆ、またはＣｌであり、
Ｒ^７は、Ｃ_１〜Ｃ_６アルキル、フェニル、Ｈｅｔ^１、Ｈｅｔ^２、Ｈｅｔ^３、またはＨｅｔ^４であり、前記Ｃ_１〜Ｃ_６アルキル、フェニル、Ｈｅｔ^１、Ｈｅｔ^２、Ｈｅｔ^３、またはＨｅｔ^４は、（ａ）Ｒ^ａ、−ＯＲ^ｂ、−Ｓ（Ｏ）_ｎＲ^ｂ、−ＣＯＲ^ｂ、−ＮＲ^ｘＲ^ｂ、−ＯＣＯＲ^ｂ、−ＣＯＯＲ^ｂ、−ＮＲ^ｘＣＯＲ^ｂ、−ＣＯＮＲ^ｘＲ^ｂ、−ＮＲ^ｘＳＯ_２Ｒ^ｂ、−ＳＯ_２ＮＲ^ｘＲ^ｂ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＲ^ｂ、−ＮＲ^ｘＣＯＯＲ^ｂ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｂ、−ＯＣＯＮＲ^ｘＲ^ｂ、−ＯＣＯＯＲ^ｂ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｂ、オキソ、および−ＣＮから選択される１〜３個の置換基で置換されていてもよく、さらに（ｂ）１個または複数のハロ原子で置換されていてもよく、
Ｒ^ａは、各場合において、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８はそれぞれ、Ｒ^ｃ、−ＯＲ^ｄ、−Ｓ（Ｏ）_ｎＲ^ｄ、−ＣＯＲ^ｄ、−ＮＲ^ｘＲ^ｄ、−ＯＣＯＲ^ｄ、−ＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＲ^ｄ、−ＣＯＮＲ^ｘＲ^ｄ −ＮＲ^ｘＳＯ_２Ｒ^ｄ、−ＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＯＲ^ｄ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｄ、オキソ、および−ＣＮから選択される１〜３個の置換基、ならびに１個または複数のハロ原子で置換されていてもよく、
Ｒ^ｂは、各場合において、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^１、Ｈｅｔ^５、Ｈｅｔ^６、Ｈｅｔ^７、およびＨｅｔ^８はそれぞれ、Ｒ^ｃ、−ＯＲ^ｄ、−Ｓ（Ｏ）_ｎＲ^ｄ、−ＣＯＲ^ｄ、−ＮＲ^ｘＲ^ｄ、−ＯＣＯＲ^ｄ、−ＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＲ^ｄ、−ＣＯＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＳＯ_２Ｒ^ｄ、−ＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＲ^ｄ、−ＮＲ^ｘＣＯＯＲ^ｄ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＮＲ^ｘＲ^ｄ、−ＯＣＯＯＲ^ｄ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｄ、オキソ、および−ＣＮから選択される１〜３個の置換基、ならびに１個または複数のハロ原子で置換されていてもよく、
ｎは、０、１または２であり、
Ｒ^ｘは、各場合において、それぞれ独立に、Ｈ、Ｃ_１〜Ｃ_６アルキル、またはＣ_３〜Ｃ_８シクロアルキルであり、前記Ｃ_１〜Ｃ_６アルキルまたはＣ_３〜Ｃ_８シクロアルキルは、１個または複数のハロ原子で置換されていてもよく、
Ａｒｙｌ^１は、フェニルまたはナフチルであり、
Ｈｅｔ^１は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、３〜８員の飽和または部分的不飽和の単環式複素環であり、但し、Ｈｅｔ^１は、ピペリジニル、ピロリジニル、およびアゼチジニルではなく、
Ｈｅｔ^２は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、６〜１２員の飽和または部分的不飽和の多環式複素環であり、但し、Ｈｅｔ^２は、架橋ピペリジニル、ピロリジニル、またはアゼチジニル環ではなく、
Ｈｅｔ^３は、（ｉ）１〜３個のＮ原子を含んでいる６員芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる５員芳香族複素環であり、
Ｈｅｔ^４は、（ｉ）１〜４個のＮ原子を含んでいる１０員二環式芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる９員二環式芳香族複素環であり、
Ｈｅｔ^５は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、３〜８員の飽和または部分的不飽和の単環式複素環であり、
Ｈｅｔ^６は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、６〜１２員の飽和または部分的不飽和の多環式複素環であり、
Ｈｅｔ^７は、（ｉ）１〜３個のＮ原子を含んでいる６員芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる５員芳香族複素環であり、
Ｈｅｔ^８は、（ｉ）１〜４個のＮ原子を含んでいる１０員二環式芳香族の複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる９員二環式芳香族複素環であり、
Ｒ^ｃは、各場合において、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２はそれぞれ、Ｒ^ｅから選択される１〜３個の置換基、および１個または複数のハロ原子で置換されていてもよく、
Ｒ^ｄは、各場合において、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２からそれぞれ独立に選択され、前記Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_８シクロアルキル、Ｃ_６〜Ｃ_１２ビシクロアルキル、Ａｒｙｌ^２、Ｈｅｔ^９、Ｈｅｔ^１０、Ｈｅｔ^１１、およびＨｅｔ^１２はそれぞれ、Ｒ^ｅから選択される１〜３個の置換基、および１個または複数のハロ原子で置換されていてもよく、
Ａｒｙｌ^２は、フェニルまたはナフチルであり、
Ｈｅｔ^９は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、３〜８員の飽和または部分的不飽和の単環式複素環であり、
Ｈｅｔ^１０は、ＯおよびＮから選択される１または２個のヘテロ原子を含んでいる、６〜１２員の飽和または部分的不飽和の多環式複素環であり、
Ｈｅｔ^１１は、（ｉ）１〜３個のＮ原子を含んでいる６員芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる５員芳香族複素環であり、
Ｈｅｔ^１２は、（ｉ）１〜４個のＮ原子を含んでいる１０員二環式芳香族複素環、または（ｉｉ）（ａ）１〜４個のＮ原子または（ｂ）１個のＯもしくはＳ原子および０〜３個のＮ原子を含んでいる９員二環式芳香族複素環であり、
Ｒ^ｅは、−ＯＲ^ｘ、−Ｓ（Ｏ）_ｎＲ^ｘ、−ＣＯＲ^ｘ、−ＮＲ^ｘＲ^ｘ、−ＯＣＯＲ^ｘ、−ＣＯＯＲ^ｘ、−ＮＲ^ｘＣＯＲ^ｘ、−ＣＯＮＲ^ｘＲ^ｘ、−ＮＲ^ｘＳＯ_２Ｒ^ｘ、−ＳＯ_２ＮＲ^ｘＲ^ｘ、−ＮＲ^ｘＳＯ_２ＮＲ^ｘＮＲ^ｘ、−ＮＲ^ｘＣＯＯＲ^ｘ、−ＮＲ^ｘＣＯＮＲ^ｘＲ^ｘ、−ＯＣＯＮＲ^ｘＲ^ｘ、−ＯＣＯＯＲ^ｘ、−ＣＯＮＲ^ｘＳＯ_２Ｒ^ｘ、オキソ、または−ＣＮである。

Alternatively, a method comprising administering a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt is provided as embodiment E1a.
Where
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, —CN, —NH ₂ , —CH ₃ , —CH ₂ F, —CHF ₂ , —CF ₃ , _-OH, -OCH _3, a -OCH ₂ F, -OCHF 2 or -OCF _3,,
R ⁶ is H, —NH ₂ , —OH, or —CH ₃ ;
R ^6a is H, F, or Cl;
R ⁷ is C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ , said C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ Are: (a) R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , —CONR ^x R ^{b _{, -NR x SO 2 R b,}} -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R b, -OCOOR b , -CONR ^x SO ₂ R ^b, oxo, and -CN may be substituted with 1-3 substituents selected from, optionally substituted with further (b) 1 one or more halo atoms Often,
R ^a is independently from each other C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ^{8 in} each case. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ⁸ are R ^c , —OR, respectively. _{^{d, -S (O) n R}} d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d -NR x SO 2 R d, -SO _{^{2 NR x R d, -NR x}} SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR d, CONR ^x SO ₂ R ^d, oxo, and one to three substituents selected from -CN, and may be substituted with one or more halo atoms,
R ^b is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ and Het ⁸ respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 1, Het 5, Het} 6, Het 7, and Het ^{8 each, R} c, _{^{-OR d, -S (O) n}} R d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d, -NR x SO 2 R d _{^{, -SO 2 NR x R d,}} -NR x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR optionally substituted by 1 to 3 substituents selected from ^{d 1} , —CONR ^x SO ₂ R ^d , oxo, and —CN, and one or more halo atoms,
n is 0, 1 or 2;
R ^x is, independently in each case, H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl is 1 Optionally substituted with one or more halo atoms,
Aryl ¹ is phenyl or naphthyl;
Het ¹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ¹ is piperidinyl , Not pyrrolidinyl and azetidinyl
Het ² is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ² is a bridged Not a piperidinyl, pyrrolidinyl, or azetidinyl ring,
Het ³ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁴ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
Het ⁵ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁶ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁷ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁸ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 A 9-membered bicyclic aromatic heterocycle containing O or S atoms and 0-3 N atoms,
R ^c is independently in each case from C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ^12. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² are each selected from R ^e Optionally substituted with 1 to 3 substituents and one or more halo atoms,
R ^d is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 2, Het 9, Het} 10, Het 11, and ^{Het 12} each, from ^{R e} Optionally substituted with 1-3 selected substituents, and one or more halo atoms,
Aryl ² is phenyl or naphthyl;
Het ⁹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹⁰ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹¹ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ¹² may be (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^{e _{is, -OR x, -S (O)}} n R x, -COR x, -NR x R x, -OCOR x, -COOR x, -NR x COR x, -CONR x R x, -NR x _{^{SO 2 R x, -SO 2 NR}} x R x, -NR x SO 2 NR x NR x, -NR x COOR x, -NR x CONR x R x, -OCONR x R x, -OCOOR x, -CONR x SO ₂ R ^x, oxo, or -CN,.

At least the disease or condition in part mediated by prostaglandin D ₂ generated by the H-PGDS is allergy or respiratory condition, e.g., allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, rhinitis disease, All types of asthma, chronic obstructive pulmonary disease (COPD), chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, etc. Exacerbation of airway hyperresponsiveness, pulmonary hypertension related airway disease, acute lung injury, bronchodilation, sinusitis, allergic conjunctivitis, or atopic dermatitis, especially asthma or chronic obstructive lung It is preferably a disease.

  Asthma types include atopic asthma, non-atopic asthma, allergic asthma, atopic IgE mediated bronchial asthma, bronchial asthma, essential asthma, intrinsic asthma, pathological condition Endogenous asthma caused by physiological disorders, extrinsic asthma caused by environmental factors, essential asthma of unknown or unknown cause, bronchitis asthma, emphysema asthma, exercise-induced asthma, allergen-induced asthma, cold-induced asthma Infectious asthma caused by occupational asthma, bacterial, fungal, protozoan, or viral infections, non-allergic asthma, early asthma, infant wheezing syndrome, and bronchitis.

  The use of a compound of formula (I) for the treatment of asthma includes asthma symptoms and conditions, such as wheezing, cough, shortness of breath, chest tightness, shallow or fast breathing, nose opening (nostril size is breathing Spreading with), depression (the neck area and between or below the ribs move inward with breathing), cyanosis (the skin starts around the mouth and becomes gray or bluish in color), runny nose or stuffy nose Palliative treatment of headaches.

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in any of the uses, methods or compositions as defined above, another compound having pharmacological activity, Also provided are those used in combination with one of the compounds listed in Table 1 below. Specific combinations that can be used in accordance with the present invention include compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and (i) a glucocorticosteroid or DAGR (corticoid receptor dissociation property). Agonists), (ii) β ₂ agonists, for example, long acting β ₂ agonists, (iii) muscarinic M3 receptor antagonists or anticholinergics, (iv) histamine receptor antagonists (H1 antagonists) may be H3 antagonists in medicine), (v) 5-lipoxygenase inhibitor, a combination comprising a (vi) a thromboxane inhibitor, or (vii) LTD ₄ inhibitors. In general, the compounds of the combination will be administered together as a formulation, together with one or more pharmaceutically acceptable excipients.

Table I
(A) a 5-lipoxygenase activating protein (FLAP) antagonist,
(B) leukotriene antagonists (LTRA), including antagonists of LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ ;
(C) histamine receptor antagonists including H1 and H3 antagonists,
(D) an α ₁ and α ₂ adrenergic receptor agonist vasoconstrictor sympathomimetic agonist for use as a decongestant;
(E) a muscarinic M3 receptor antagonist or anticholinergic agent,
(F) PDE inhibitors such as theophylline, such as PDE3, PDE4, and PDE5 inhibitors,
(G) sodium cromoglycate,
(H) COX inhibitor inhibitors, both non-selective and selective COX-1 or COX-2 inhibitors (such as NSAIDs),
(I) Glucocorticosteroids or DAGR (corticoid receptor dissociating agonist),
(J) a monoclonal antibody active against endogenous inflammatory entities;
(K) β2 agonists including long acting β2 agonists,
(L) an integrin antagonist,
(M) adhesion molecule inhibitors including VLA-4 antagonists,
(N) kinin B ₁ and B ₂ receptor antagonists,
(O) IgE pathway inhibitors and immunosuppressants including cyclosporine,
(P) inhibitors of matrix metalloproteinases (MMP) such as MMP9 and MMP12;
(Q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,
(R) protease inhibitors such as elastase inhibitors, chymase, and cathepsin G;
(S) an adenosine A2a receptor agonist and an A2b antagonist;
(T) an inhibitor of urokinase,
(U) a compound acting on a dopamine receptor, such as a D2 agonist,
(V) a modulator of the NFκB pathway, such as an IKK inhibitor,
(W) modulators of cytokine signaling pathways such as syk kinase, JAK kinase inhibitor, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R, MK-2,
(X) drugs that can be classified as mucolytic or antitussives, and mucokinetics;
(Y) antibiotics,
(Z) an antiviral agent,
(Aa) vaccine,
(Bb) chemokine,
(Cc) epithelial sodium channel (ENaC) blocker or epithelial sodium channel (ENaC) inhibitor,
(Dd) P2Y2 agonists and other nucleotide receptor agonists,
(Ee) an inhibitor of thromboxane,
(Ff) Niacin,
(Gg) inhibitors of 5-lipoxygenase (5-LO), and (hh) adhesion factors including VLAM, ICAM, and ELAM.

  In addition to being useful for human treatment, the compounds of formula (I) are also useful for veterinary treatment of companion animals, exotic animals, and livestock.

As used in this application, the following abbreviations have the meanings set forth below.
APCI (for mass spectrometry) is atmospheric pressure chemical ionization,
BOC or Boc is tert-butyloxycarbonyl;
BOP is (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate;
CDI is 1,1-carbonyldiimidazole;
CH ₂ Cl ₂ is dichloromethane,
CO ₂ Et is ethyl carboxylate;
DCC is N, N′-dicyclohexylcarbodiimide,
DCM is dichloromethane,
CDCl ₃ is deuterated chloroform,
DEA is diethylamine,
DIEA is diisopropylethylamine,
DIPEA is N, N-diisopropylethylamine,
DMA is N, N-dimethylacetamide,
DMAP is 4-dimethylaminopyridine,
DMF is dimethylformamide;
DMSO is dimethyl sulfoxide,
DMSO-d ₆ is fully deuterated dimethyl sulfoxide;
EDC / EDAC is N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride,
ES (for mass spectrometry) is electrospray,
Et is ethyl;
EtOAc is ethyl acetate,
GCMS is gas chromatography mass spectrometry,
h is time,
HATU is N, N, N ′, N′-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate;
HBTU is N, N, N ′, N′-tetramethyl-O- (1H-benzotriazol-1-yl) uronium hexafluorophosphate;
IH NMR or ¹ H NMR is proton nuclear magnetic resonance,
HOAt is 1-hydroxy-7-azabenzotriazole,
HOBt is 1-hydroxybenzotriazole,
HPLC is high performance liquid chromatography
HRMS is high resolution mass spectrometry,
IPA is isopropyl alcohol,
iPr is isopropyl;
LCMS is liquid chromatography mass spectrometry
LRMS is low resolution mass spectrometry,
Me is methyl,
MeCN is acetonitrile,
MeOH is methanol,
MeOD-d ₄ is fully deuterated methanol,
MgSO ₄ is magnesium sulfate,
min is the minute,
NH ₄ Cl is ammonium chloride;
NH ₄ OH is an aqueous ammonia solution,
MS is mass spectrometry,
NMM is 4-methylmorpholine,
NMP is N-methylpyrrolidinone,
RT is the holding time,
TBTU is O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate
TEA is triethylamine,
TFA is trifluoroacetic acid,
THF is tetrahydrofuran.

  Unless defined otherwise herein, scientific and technical terms used in connection with the present invention should have the meanings that are commonly understood by those of ordinary skill in the art.

  The phrase “therapeutically effective” is intended to describe the amount of the compound or pharmaceutical composition or, in the case of combination therapy, the amount of active ingredients combined. The amount or combined amount will achieve the treatment goal for the condition.

  The term “treatment”, as used herein to describe the invention, and unless otherwise limited, administers a compound, pharmaceutical composition, or combination to prevent, palliative, supportive, recovery. It means to realize a propulsive or curative treatment. The term treatment encompasses any objective or subjective improvement in a subject with respect to the condition or disease in question.

  The term “prophylactic treatment”, as used herein to describe the present invention, has a substantial predisposition to administration of a compound, pharmaceutical composition, or combination to a subject, particularly a condition of interest. It means to suppress or prevent the occurrence of a corresponding condition in a group subject or member.

  The term “palliative treatment”, as used herein to describe the present invention, does not necessarily indicate the progression of the condition or the underlying etiology of administration of a compound, pharmaceutical composition, or combination to a subject. Means to cure the signs and / or symptoms of the condition without correction.

  The term “supportive treatment”, as used herein to describe the present invention, administers a compound, pharmaceutical composition, or combination to a subject as part of a regimen of therapy, It is meant not to be limited to administration of the compound, pharmaceutical composition, or combination. Unless stated otherwise, supportive treatment includes prophylactic, palliative, recovery promoting, or curative treatment, particularly when the compound or pharmaceutical composition is combined with another component of supportive care. There is also.

  The term “recovery-promoting treatment” as used herein to describe the invention modifies the underlying progression or pathogenesis of a condition by administering a compound, pharmaceutical composition, or combination to a subject. Means that. Non-limiting examples include, and are related to, increased 1-second forced expiratory volume (FEV1) of lung disorders, slowing the rate of lung function decline over time, suppression of progressive nerve destruction, disease or disorder Reduction of certain biomarkers, reduction of recurrence, improvement of quality of life, shortening of hospital stay during acute exacerbation events.

  The term “curative treatment” as used herein to describe the invention, administration of a compound, pharmaceutical composition, or combination to a subject for complete amelioration of the disease or disorder, or It means that no disease or disorder is detected after such treatment.

The term “alkyl”, alone or in combination, means an acyclic saturated hydrocarbon group of formula C _n H _{2n + 1} , which may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl. Unless otherwise specified, alkyl groups contain 1-6 carbon atoms.

The term “alkylene” means a divalent acyclic saturated hydrocarbon group of formula C _n H _2n , which may be linear or branched. Examples of such _{groups, -CH 2 -, - CH (} CH 3) -, - CH 2 CH 2 -, - CH (CH 3) CH 2 -, - CH (CH 3) CH (CH 3) - , and _-CH 2 _CH 2 CH ₂ - and the like. Unless otherwise specified, alkyl groups contain 1-6 carbon atoms.

The number of carbon atoms in the alkyl and other various hydrocarbon-containing moieties is indicated by a prefix meaning the number of carbon atoms below or above that moiety, i.e., the prefix C _i -C _j is the integer “ i ”to“ j ”(including i and j) carbon atoms. Thus, for example, C ₁ -C ₆ alkyl refers to alkyl of 1 to 6 (including 1 and 6) carbon atoms.

  The term “hydroxy” as used herein means an OH radical.

Het ¹ , Het ⁵ and Het ⁹ are saturated or partially saturated (ie, non-aromatic) heterocycles that are attached via a ring carbon atom, even if attached via a ring nitrogen atom. It may be. Similarly, when substituted, the substituent may be located on the ring nitrogen atom or on the ring carbon atom. Specific examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl, and diazepinyl.

Het ² , Het ⁶ and Het ¹⁰ are saturated or partially saturated heterocycles which may be bonded via a ring nitrogen atom or via a ring carbon atom. Similarly, when substituted, the substituent may be located on the ring nitrogen atom or on the ring carbon atom. Het ² , Het ⁶ and Het ¹⁰ are polycyclic heterocyclic groups containing two or more rings. Such rings may be linked to form a bridged, fused, or spiro-fused ring system, as exemplified below with two 6-membered rings (heteroatoms are not shown).

Ｈｅｔ^２、Ｈｅｔ^６およびＨｅｔ^１０は、完全に飽和していても、部分的不飽和でもよく、すなわち、１以上の不飽和度を有する場合もあるが、完全に芳香族になることはない。縮合環系の場合では、環の一方が芳香族である場合もあるが、その両方がそうなることはない。Ｈｅｔ^２の例は、トロパニル（アザビシクロ［３．２．１］オクタニル）である。

Het ² , Het ⁶ and Het ¹⁰ may be fully saturated or partially unsaturated, i.e. may have one or more degrees of unsaturation, but never become completely aromatic. In the case of fused ring systems, one of the rings may be aromatic, but not both. An example of Het ² is tropanyl (azabicyclo [3.2.1] octanyl).

Het ³ , Het ⁷ and Het ¹¹ are aromatic heterocycles which may be bonded via a ring carbon atom or a ring nitrogen atom having an appropriate valence. Similarly, when substituted, the substituent may be located on a ring carbon atom or a ring nitrogen atom having the appropriate valence. Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

Het ⁴ , Het ⁸ and Het ¹² are aromatic heterocycles which may be attached via a ring carbon atom or a ring nitrogen atom having an appropriate valence. Similarly, when substituted, the substituent may be located on a ring carbon atom or a ring nitrogen atom having the appropriate valence. Het ⁴ and Het ⁸ are aromatic and thus inevitably become fused bicycles. Specific examples include benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo [2,3-b] pyridyl, pyrrolo [2,3-c] pyridyl, pyrrolo [3,2-c] pyridyl Pyrrolo [3,2-b] pyridyl, imidazo [4,5-b] pyridyl, imidazo [4,5-c] pyridyl, pyrazolo [4,3-d] pyridyl, pyrazolo [4,3-c] pyridyl Pyrazolo [3,4-c] pyridyl, pyrazolo [3,4-b] pyridyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, pyrazolo [1,5-a] pyridyl, pyrrolo [1,2-b] pyridazinyl, imidazo [1,2-c] pyrimidinyl, quinolinyl, isoquinone Linyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido [3 2-d] pyrimidinyl, pyrido [4,3-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [2,3-d] pyrimidinyl, pyrido [2,3-d] pyrazinyl, pyrido [3 4-b] pyrazinyl, pyrimido [5,4-d] pyrimidinyl, pyrazino [2,3-b] pyrazinyl, and pyrimido [4,5-d] pyrimidine.

The term “cycloalkyl” means a monocyclic saturated hydrocarbon group of formula C _n H _2n-1 . Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, cycloalkyl groups contain 3-8 carbon atoms.

The term bicycloalkyl means a bicyclic saturated hydrocarbon group of the formula C _n H _{2n-3 in which} the two rings are linked in a fused, spiro-fused or bridged manner (see above). To do. The following groups are illustrative of C ₅ -C ₁₂ bicycloalkyl (note that these groups have an extra hydrogen atom that should be a bond as depicted).

In the definition of R ⁷ , the C ₃ -C ₈ cycloalkyl ring may be fused to a phenyl ring or a 5 or 6 membered aromatic heterocycle. In such a condensation, the R ⁷ group may be bound to the amide nitrogen in the cycloalkyl ring or fused ring, but is preferably bound in the cycloalkyl ring. Similarly, when the R ⁷ group is substituted, the substitution may be on the cycloalkyl ring, the fused ring, or both. The 5- or 6-membered aromatic heterocycle is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) It is preferably a 5-membered aromatic heterocycle containing one O or S atom and 0 to 3 N atoms. Detailed examples of preferred 5- or 6-membered aromatic heterocycles are given above for Het ³ / Het ⁷ . When the C ₃ -C ₈ cycloalkyl ring of R ⁷ is fused, it is particularly preferred that it is fused to a phenyl, imidazolyl, pyridyl, or pyrazolyl ring.

  The term “oxo” means a double bonded oxygen.

  The term “alkoxy” means a radical comprising an alkyl radical attached to an oxygen atom, such as a methoxy radical. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

As used herein, the terms “co-administration”, “co-administer”, and “in combination” refer to the following for a combination of a compound of formula (I) and one or more other therapeutic agents: It is intended to include and refer to the following:
Co-administration of such a combination of a compound of formula (I) and another therapeutic agent to a patient in need of treatment (wherein such components are formulated together in a single dosage form, From the dosage form, the component is released to the patient at substantially the same time),
Substantially simultaneous administration of such a combination of a compound of formula (I) and another therapeutic agent to a patient in need of treatment (wherein such components are formulated in separate dosage forms apart from one another) A separate dosage form is used by the patient at substantially the same time and then the component is released to the patient at substantially the same time), and ● different from the compound of formula (I) Sequential administration of such combinations of therapeutic agents to a patient in need of treatment (in which case such components are formulated separately from one another in separate dosage forms, each separated by the patient Used continuously with considerable time intervals between administrations, after which the component is released to the patient at substantially different times), and ● of the compound of formula (I) and another therapeutic agent Sequential administration of such combinations to patients in need of treatment (At this time, such components are formulated together into a single dosage form, a single dosage form, wherein the component is released in a controlled manner).

  The term “excipient” is used to describe any ingredient other than the compound of formula (I). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the type of dosage form. The term “excipient” includes diluents, carriers, or adjuvants.

  Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

  Suitable acid addition salts are those generated from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, cyclamic acid Salt, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / Bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotine Acid salt, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, sugar salt, stearate, succinic acid Salt, tannate, tartar Salt, tosylate, trifluoroacetate, naphthalene-1,5-disulfonic acid, and Kishinoho acid salts.

  Suitable base salts are those generated from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, allamine, potassium, sodium, tromethamine, and zinc salts.

  Acid and base half salts may be produced, such as hemisulfate and half calcium salts. For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002) by Stahl and Wermuth.

Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of the following three methods.
(I) a method by reacting a compound of formula (I) with the desired acid or base;
(Ii) removing the acid or base labile protecting group from the appropriate precursor of the compound of formula (I) using the desired acid or base, or the appropriate cyclic precursor, eg lactone Or by ring opening of lactams, or (iii) by converting a salt of a compound of formula (I) into another salt by reaction with a suitable acid or base, or by a suitable ion exchange column Method.

  All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from complete ionization to little ionization.

  The compounds of formula (I) may also exist in unsolvated or solvated forms. The term “solvate” as used herein refers to a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, such as ethanol. Used to describe. The term “hydrate” is used when the solvent is water.

  Currently accepted classification systems for organic hydrates are those that define isolated site hydrates, channel hydrates, or metal ion coordination hydrates. K. R. See "Polymorphism in Pharmaceutical Solids" by Morris (edited by HG Brittain, Marcel Dekker, 1995). Isolation site hydrates are hydrates in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules are located in lattice channels where they are adjacent to other water molecules. In metal ion coordination hydrate, water molecules are bound to metal ions.

  When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry regardless of humidity. However, when the solvent or water bond is weak, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry is the norm.

  Within the scope of the present invention are multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter is usually defined as a crystalline complex consisting of neutral molecular components joined together by non-covalent interactions, but may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically rubbing the components. O. Almarsson and M.M. J. et al. See Chem Commun, 17, 1889-1896 (2004) by Zawortko. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288 (August 1975) by Halebrian.

  The compounds of the present invention may exist in a series of solid states ranging from fully amorphous to fully crystalline. The term “amorphous” refers to a state in which a material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such materials are described more formally as liquids, while not giving a characteristic X-ray diffraction pattern and exhibiting solid properties. Upon heating, a change from a solid property to a liquid property occurs, but is usually characterized by a secondary state change ("glass transition"). The term “crystal” refers to a solid phase in which the material has a regular and ordered internal structure at the molecular level and gives a characteristic X-ray diffraction pattern with well-defined peaks. Such materials also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is usually characterized by a first order phase change ("melting point").

Compounds of formula (I) may exist in an intermediate state (as mesophase or liquid crystal) when placed under appropriate conditions. The intermediate state is between the true crystal state and the true liquid state (melt or solution). The intermediate state resulting from the temperature change is described as “temperature transition type”, and the intermediate state resulting from adding a second component such as water or another solvent is “concentration transition type”. Described. Compounds with the potential to produce concentration-transition mesophases are described as “amphiphilic” and are ionic (—COO ⁻ Na ⁺ , —COO ⁻ K ⁺ , —SO ₃ ⁻ Na ⁺ Etc.) or nonionic (such as —N ^— N ⁺ (CH ₃ ) ₃ ) polar molecules. For more information, see N.C. H. Harthorne and A.H. See "Crystals and the Polarizing Microscope" by Stuart, 4th edition (Edward Arnold, 1970).

  In the following, all references to compounds of formula (I) (also referred to as compounds of the invention) are all their salts, solvates, multicomponent complexes and liquid crystals, and solvates of their salts, multicomponent complexes. And references to liquid crystals.

  Within the scope of the present invention are all polymorphs and crystal habits of the compounds of formula (I), their prodrugs and isomers (optical isomers, geometric isomers, and tautomers, as defined below) As well as isotopically labeled forms thereof.

  As indicated, so-called “prodrugs” of the compounds of formula (I) are also within the scope of the invention. Thus, certain derivatives of compounds of formula (I), which may themselves have little or no pharmacological activity, can be obtained when administered in or on the body, for example by cleavage by hydrolysis. It can be converted to a compound of formula (I) having activity. Such derivatives are referred to as “prodrugs”. More information on the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems”, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella), and “Bioreversible Carriers in Dragons 1987 (EB Roche, edited by American Pharmacists Association).

  Prodrugs according to the invention can be prepared, for example, from suitable functional groups present in compounds of the formula (I), for example H.P. As described in “Design of Prodrugs” by Bundgaard (Elsevier, 1985), it can be produced by exchanging with a specific part known to those skilled in the art as a “pro-part”.

Some examples of prodrugs according to the present invention include:
(I) When the compound of formula (I) contains a carboxylic acid functional group (—COOH), the ester, for example, the hydrogen of the carboxylic acid functional group of the compound of formula (I) is (C ₁ -C ₈ ) Compounds exchanged for alkyl,
(Ii) when the compound of formula (I) contains an alcohol functional group (—OH), the ether, for example, the hydrogen of the alcohol functional group of the compound of formula (I) is (C ₁ -C ₆ ) alkanoyloxy When the compound exchanged with methyl, and (iii) the compound of formula (I) contains a primary or secondary amino function (—NH ₂ or —NHR (where R ≠ H)) A compound in which the amide, for example one or both hydrogens of the amino function of the compound of formula (I) is optionally replaced with (C ₁ -C ₁₀ ) alkanoyl.

  Another example of a replacement group according to the previous example, and other examples of prodrug types can be found in the references cited above.

  Also, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

  Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Where structural isomers are interconvertible with a low energy barrier, tautomeric isomerism ("tautomerism") may exist. Tautomerism can take the form of, for example, proton tautomerism for compounds of formula (I) containing imino, keto, or oxime groups, or so-called valence tautomerism for compounds containing aromatic moieties. . This means that a single compound may exhibit multiple types of isomerism.

  Within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of compounds of formula (I), including compounds exhibiting more than one isomerism, and one or more of these A mixture of Also included are acid addition salts or base salts in which the counterion is optically active, such as d-lactic acid or l-lysine, or a racemate, such as dl-tartaric acid or dl-arginine.

  Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

  Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from optically pure suitable precursors, or racemates using, for example, chiral high pressure liquid chromatography (HPLC) (Or racemic salt or derivative). Alternatively, the racemate (or racemic precursor) can be converted to a suitable optically active compound such as an alcohol or 1-phenyl when the compound of formula (I) contains an acidic or basic moiety. It can also be reacted with a base or acid such as ethylamine or tartaric acid. The resulting diastereoisomeric mixture is separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers are converted to the corresponding pure enantiomers by means well known to those skilled in the art. can do. The chiral compound of formula (I) (and its chiral precursor) is 0-50% by volume, usually 2% -20% alcohol solvent, such as isopropanol, and 0-5% by volume alkylamine, usually Obtain in enantiomerically enriched form using chromatography on asymmetric resins, usually HPLC, with a mobile phase consisting of a hydrocarbon containing 0.1% diethylamine, usually heptane or hexane. Can do. Concentration of the eluate provides a concentrated mixture. Chiral chromatography using subcritical and supercritical fluids may be used. Chiral chromatographic methods useful in some embodiments of the present invention are known in the art (eg, Smith, Roger M., Loughborough University, Loughborough, UK, Chromatographic Science Series (1998), 75 (Supric). Fluid Chromatography with Packed Columns), pages 223-249, and references cited therein). In some relevant examples herein, the columns were obtained from Chiral Technologies, Inc., a subsidiary of Daicel Chemical Industries, Ltd. (Tokyo), West Chester, Pennsylvania, USA.

  When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) referred to above, which produces one homogeneous form of crystal containing both enantiomers in equimolar amounts. The second type is a racemic mixture or assembly, in which two forms of crystals, each containing a single enantiomer, are produced in equimolar amounts. Both crystal forms present in the racemic mixture have the same physical properties, but these crystal forms may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. For example, E.I. L. Eliel and S.M. H. See "Stereochemistry of Organic Compounds" by Wilen (Wiley, 1994).

  The present invention relates to a pharmaceutically acceptable wherein one or more atoms are exchanged for an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. All possible isotopically-labelled compounds of formula (I) are included. Isotopically-labelled compounds of formula (I) generally use conventional isotopes known to those skilled in the art, using appropriate isotope-labeled reagents instead of previously unlabeled reagents. It can be prepared by techniques or by methods analogous to those described in the appended examples and preparations.

Also included within the scope of the present invention are metabolites of compounds of formula (I), that is, compounds that are generated in vivo when a drug is administered. Some examples of metabolites according to the present invention include:
(I) when the compound of formula (I) contains a methyl group, its hydroxymethyl derivative (—CH ₃ → —CH ₂ OH),
(Ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (—OR → —OH),
(Iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (—NR ¹ R ² → —NHR ¹ or —NHR ² ),
(Iv) when the compound of formula (I) contains a secondary amino group, its primary derivative (—NHR ¹ → —NH ₂ ),
(V) if the compound of formula (I) contains a phenyl moiety, the phenol derivative (-Ph → -PhOH), and (vi) if the compound of formula (I) contains an amide group, Acid derivative (—CONH ₂ → COOH).

  For administration to human patients, the total daily dose of the compound of formula (I) is usually in the range of 0.01 mg to 500 mg, depending on the mode of administration. In another embodiment of this invention, the total daily dose of a compound of formula (I) is typically in the range of 0.1 mg to 300 mg. In yet another embodiment of the present invention, the total daily dose of a compound of formula (I) is usually in the range of 1 mg to 30 mg. The total daily dose can be administered as a single dose or in divided doses and may deviate from the normal ranges shown herein under the direction of the physician. These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a filled capsule, blister, or pocket, or by a system that utilizes a dosing chamber that is fed gravimetrically. Units according to the invention are usually arranged to administer a metered dose or “puff” containing 1 to 5000 μg of drug. The overall daily dose will usually be in the range 1 μg to 20 mg, which may be administered once, or more usually in several divided doses throughout the day.

  The compound of formula (I) may be administered per se or in the form of a pharmaceutical composition, the pharmaceutical composition being added to conventional pharmaceutically harmless excipients and / or additives. In addition, the active ingredient contains an effective dose of at least one compound of the invention.

  Pharmaceutical compositions suitable for delivery of the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

  The compound of formula (I) can be administered orally. Oral administration may be swallowed so that the compound enters the gastrointestinal tract, or buccal or sublingual administration where the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets; capsules containing microparticles, liquids or powders; lozenges (including liquid-filled types), chewing agents, multiparticulates and nanoparticles, gels, solid solutions, liposomes , Films, vaginal suppositories, sprays, and liquid formulations. Oral administration, particularly in the form of tablets or capsules, is preferred for compounds of formula (I).

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can also be used as fillers in soft or hard capsules, usually a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil and one or more emulsifiers. And / or a suspending agent. Liquid preparations can also be prepared, for example, by reconstitution of solids from sachets.

  Compounds of formula (I) may also be used in rapidly dissolving and rapidly disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001). it can.

  In tablet dosage forms, depending on dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally also contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, α Modified starch, and sodium alginate. Generally, the disintegrant will comprise 1% to 25% by weight. In one embodiment of the invention, the disintegrant will comprise 5% to 20% by weight of the dosage form. Binders are commonly used to impart adhesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets are diluents such as lactose (monohydrate, spray-dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dicalcium phosphate dihydrate, etc. May also be included. Tablets may also optionally contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. If present, the surfactant may comprise from 0.2% to 5% by weight of the tablet and the lubricant may comprise from 0.2% to 1% by weight of the tablet. Tablets generally also contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.25% to 10% by weight. In one embodiment of the invention, the lubricant comprises 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and flavoring agents.

  Exemplary tablets have up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegration. And about 0.25 wt% to about 10 wt% lubricant.

  Tablet blends can be formed by compressing the tablet blend directly or by roller. Alternatively, the tablet blend or portion of the blend can be tableted after being subjected to wet, dry, or melt granulation, melt coagulation, or extrusion processing. The final formulation may include single or multiple layers, may or may not be coated, and may be encapsulated. For tablet formulations, see H.C. Lieberman and L.L. Discussed in “Pharmaceutical Dosage Forms: Tablets” by Lachman, Volume 1 (Marcel Dekker, New York, 1980).

  Ingestible oral films for use in human or veterinary medicine are usually flexible water-soluble or water-swellable thin film dosage forms, which may be fast dissolving or mucoadhesive, and are usually compounds of formula (I) , Film forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Some components of the formulation may perform multiple functions. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is usually in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Exists. Other possible ingredients include antioxidants, colorants, flavoring and flavoring agents, preservatives, salivary gland stimulants, cooling agents, co-solvents (including oils), relaxation agents, bulking agents, antifoaming agents, Surfactants and flavoring agents can be mentioned. Films according to the invention are usually prepared by evaporating and drying a thin water-soluble film applied to a strippable support carrier or paper. This can be done in a drying oven or drying tunnel, usually a composite coating dryer, or by freeze drying or vacuum drying.

  Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified releases include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. A modified release formulation suitable for the purposes of the present invention is described in US Pat. No. 6,106,864. Details of other suitable release technologies, such as high energy dispersion and osmotic and coated particles, can be found in Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) by Verma et al. The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of formula (I) can also be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle syringes (including microneedles), needleless syringes, and infusion techniques.

  The compounds of the invention can also be administered topically to the skin or mucosa, ie dermally or transdermally.

  The compound of formula (I) is usually a dry powder inhaler in the form of a dry powder (either alone, for example as a mixture in a dry blend with lactose or as mixed component particles, eg mixed with a phospholipid such as phosphatidylcholine). A pressurized container, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, It can also be administered as an aerosol spray from a pump, spray, atomizer (preferably an atomizer that uses electrohydraulics to generate a fine mist), or as a nebulizer, or as a nasal spray, intranasally or by inhalation. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or another substance suitable for dispersing, solubilizing, or extending the release of a compound, propellant as a solvent, As well as solutions or suspensions of the compound of formula (I), including optional surfactants such as sorbitan trioleate, oleic acid, oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, spray drying and the like.

  Capsules (eg, made of gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in an inhaler or infuser are powder mixtures of the compounds of the invention, suitable powder bases such as lactose and starch, And can be formulated to contain performance modifiers such as l-leucine, mannitol, magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, but the latter is preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A solution formulation suitable for use in an atomizer that uses electrohydraulics to generate a fine mist may contain 1 μg to 20 mg of the compound of the invention per actuation, and the actuation volume may vary from 1 μl to 100 μl. . A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Appropriate flavoring agents such as menthol and l-menthol, or sweetening agents such as saccharin and saccharin sodium may be added to such formulations of the present invention intended for intranasal administration. Formulations for intranasal administration can also be formulated for immediate and / or modified release, for example using PGLA. Modified release includes delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of formula (I) can also be administered directly to the eye or ear, usually in the form of a finely divided suspension or solution droplets in isotonic sterile saline, pH adjusted.

  A compound of formula (I) may be used to improve its solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in any of the above-described modes of administration. It can be combined with its soluble derivatives such as suitable derivatives and polyethylene glycol-containing polymers. For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can also be used as an auxiliary additive, ie as a carrier, diluent, or solubilizer. The most commonly used for such purpose are α, β and γ cyclodextrins, examples of which are WO-A-91 / 11172, WO-A-94 / 02518, and WO-A- It can be seen at 98/55148.

  Since it may be desirable to administer a combination of active compounds, eg, for the purpose of treating a particular disease or condition, two or more pharmaceutical compositions, at least one of which contains a compound of formula (I), It is within the scope of the present invention that it may be conveniently combined in the form of a kit suitable for co-administration of the composition. Accordingly, the kit of the present invention comprises one or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I), and a container, a divided bottle, a divided foil bag, etc. Means for holding the compositions separately. An example of such a kit is a familiar blister pack used for the packaging of tablets, capsules and the like. Such kits are particularly suitable for administering, for example, different oral and parenteral dosage forms, administering separate compositions at different dosing intervals, or increasing the dose of separate compositions relative to each other. To assist compliance, kits typically include directions for administration and may be provided with a so-called memory aid.

  All compounds of formula (I) can be prepared by combining the detailed and comprehensive experimental procedures described below with general knowledge common to those skilled in the art (eg, “Comprehensive Organic Chemistry”, edited by Barton and Oliss, Elsevier; See Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons).

  Compounds of formula (I) that are amides are conveniently prepared according to Scheme 1 by combining an amine of formula (III) and an acid of formula (II).

  One skilled in the art will recognize that many methods for preparing amides are known. For example, Montalbetti, C.I. A. G. N and Falque, V.M. , "Amide bond formation and peptide coupling", Tetrahedron, 2005, 61 (46), pages 10827-10852, and the references cited therein. Accordingly, the examples provided herein are illustrative only and not limiting.

The following general methods i, ii and iii were used.
(I) To a solution of carboxylic acid (0.15 mmol) and 1-hydroxybenzotriazole (0.3 mmol) in DMF (1.0 mL) was added 0.3 mmol of PS-carbodiimide resin (Argonaut, 1.3 mmol / g). It was. The mixture was shaken for 10 minutes and then a solution of amine (0.1 mmol) in DMF (1 mL) was added. The mixture was stirred at room temperature overnight and subsequently treated with 0.60 mmole PS-trisamine (Argonaut, 3.8 mmol / g). The reaction mixture was filtered, concentrated in vacuo and purified by reverse phase chromatography.
(Ii) To a solution of carboxylic acid (0.15 mmol) and HBTU (0.175 mmol) in DMF (1.0 mL) was added 0.45 mmol of triethylamine. The mixture was stirred for 30 minutes and then a solution of amine (0.2 mmol) in DMF (1.0 mL) was added. The mixture was stirred at room temperature overnight and subsequently partitioned between water and a suitable organic solvent. The organic phase was separated, concentrated in vacuo and purified by either reverse phase chromatography, normal phase chromatography, or crystallization.
(Iii) To a DMF solution of carboxylic acid (0.15 mmol), a DMF (1.0 mL) solution of N, N-carbonyldiimidazole (0.18 mmol) was added. The mixture was stirred for 30 minutes and then a solution of amine (0.18 mmol) in DMF (1.0 mL) was added. The mixture was stirred at room temperature overnight and subsequently partitioned between water and a suitable organic solvent. The organic layer was separated, concentrated in vacuo, and purified by either reverse phase chromatography, normal phase chromatography, or crystallization.

  Where a compound is described as being prepared as described for the previous examples, one skilled in the art will recognize that the reaction time, number of reagent equivalents, and reaction temperature will vary for each particular reaction. It will be appreciated that as well as it may still be necessary or desirable to use different work-up or purification conditions.

  One skilled in the art will appreciate that there are many known methods for preparing aryl pyridines of formula (II). Such methods are disclosed in patent textbooks and laboratory manuals that constitute common general knowledge for engineers, including textbooks cited above as references and references cited therein. . Usually, aryl (or heteroaryl) halides (Cl, Br, I) or trifluoromethanesulfonic acid esters, together with organometallic species such as stannane, organomagnesium derivatives, or boronic esters or boronic acids, tetrahydrofuran, toluene, In a solvent containing DMF and water, the mixture is stirred at 0 to 120 ° C. for 1 to 24 hours in the presence of a catalyst, usually palladium derivative. For example, aryl (or heteroaryl) bromide in a water / toluene mixture, a base such as sodium carbonate or sodium hydroxide, a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), tetra-n bromide Heating to 100 ° C. with a phase transfer catalyst such as butylammonium and an aryl (or heteroaryl) boronic acid or boronic ester. As a second example, aryl (or heteroaryl) boronic acid esters, aryl (or heteroaryl) halides (Cl, Br, I) or aryl (or heteroaryl) trifluoromethanesulfonic acid esters, and such as KF and CsF The fluoride source may be used in a non-aqueous reaction medium such as 1,4-dioxane. During such a coupling reaction, it may be necessary to protect the acid functionality of the compound of formula (II). Suitable protecting groups and their use are well known to those skilled in the art (see, for example, “Protective Groups in Organic Synthesis” by Theorora Greene and Peter Wuts (3rd edition, 1999, John Wiley and Sons)). .

  Amines of formula (III) are often commercially available or can be prepared by standard methods well known to those skilled in the art. See, for example, “Comprehensive Organic Transformations” (1999, VCH Publishers Inc.) by Richard Larock.

The following compounds summarized in the table were prepared using the methods described above. Data regarding purification and characterization are shown in the table, and the relevant HPLC and LCMS methods are detailed after the table, with more detailed details regarding the preparation and characterization of the selected compounds. Examples 1 to 573 are defined in accordance with Formula (Ib), where R ¹ , R ² , R ³ and R ⁵ specify different meanings for one or more of these. Each is H unless otherwise specified.

  Examples 574-583 are defined according to formula (Ic).

  Examples 584 to 591 are defined according to the formula (Id).

  Examples 587 to 591 are defined according to the formula (Ie).

  Details of the purification methods referenced in the table above are given in the following sections, along with further details on the preparation and characterization of the examples selected from the examples summarized in the table.

HPLC method E (preparative)
Purification was performed using a Waters Sunfire C18 column 20 × 50 mm × 5 μm, eluting with a water / acetonitrile / 0.1% formic acid gradient, usually 85% water to 5% water over 8 minutes. The flow rate was 30 ml / min, and mass spectrometry was used as a trigger.

LCMS method F (analysis)
Analysis was performed using a Sunfire C18 column, 2.1 × 50 mm × 5 μm. Gradient elution uses water / acetonitrile / 0.1% formic acid, a gradient of 95-5% water over 8 minutes, 1 minute hold at the end of the work, flow rate 1 mL / min, purity assessment by UV (215 nM). Carried out.

Example 1
6- (3-Fluorophenyl) -N- [2- (6-methylimidazo [1,2-a] pyridin-2-yl) ethyl] nicotinamide 6- (3-Fluorophenyl) nicotinic acid (50 mmol), HATU (50 mmol) and triethylamine (50 mmol) were dissolved in DM. 2- (6-Methyl-imidazo [1,2-a] pyridin-2-yl) ethylamine (50 mmol) was added and the solution was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by HPLC to give the title compound. Method C (analysis) and D (preparation) were used.

  Examples 2-150 were prepared similarly.

(Example 151)
To a suspension of N- (2-methylbenzyl) -6-phenylnicotinamide polymer-bound carbodiimide (0.2 mmol) in DMF (1 mL), 6-phenylnicotinic acid (30 mg, 0.15 mmol), HOBT (46 mg, 0.3 mmol), and 2-methylbezylamine (18 mg, 0.15 mmol) were added. The reaction was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC chromatography using Method E. The product was analyzed using Method F. This gave the title compound.

  Examples 152-528 were prepared similarly.

(Example 529)
6- (3-Fluorophenyl) -N-[(1R, 5S, 6s) -3-pyrimidin-2-yl-3-azabicyclo [3.1.0] hex-6-yl] nicotinamide

この実施例は、６−（３−フルオロフェニル）ニコチン酸（１００ｍｇ、０．４６ｍｍｏｌ）および（１Ｓ，５Ｒ，６Ｓ）−３−ピリミジン−２−イル−３−アザ−ビシクロ［３．１．０］ヘキサ−６−イルアミン（８１ｍｇ、０．４６ｍｍｏｌ）を使用し、ＣＤＩをカップリング剤として使用して、上記一般法のセクションに記載のとおりに調製した。生成物は、酢酸エチル／ヘプタン（１：３）を溶離液とするシリカゲルでのフラッシュクロマトグラフィーによって精製した。

This example is based on 6- (3-fluorophenyl) nicotinic acid (100 mg, 0.46 mmol) and (1S, 5R, 6S) -3-pyrimidin-2-yl-3-aza-bicyclo [3.1.0. Prepared as described in the general method section above using hexa-6-ylamine (81 mg, 0.46 mmol) and CDI as the coupling agent. The product was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane (1: 3).

(Example 534)
N-[(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl) methyl] -6- (3-fluorophenyl) nicotinamide

６−（３−フルオロフェニル）ニコチン酸（１０９ｍｇ、０．５ｍｍｏｌ）、３−アミノメチル−５−フルオロ−１，３−ジヒドロインドール−２−オン（１０８ｍｇ、０．５ｍｍｏｌ）、ＴＢＴＵ（１９３ｍｇ、０．６０ｍｍｏｌ）、およびトリエチルアミン（１５２ｍｇ、１．５ｍｍｏｌ）を、ジクロロメタン（３ｍＬ）中で終夜一緒に撹拌した。ジクロロメタン（４ｍＬ）および水（５ｍＬ）を加え、沈殿した固体を濾過し、水およびジエチルエーテルで洗浄して、１００ｍｇの生成物を得た。

6- (3-Fluorophenyl) nicotinic acid (109 mg, 0.5 mmol), 3-aminomethyl-5-fluoro-1,3-dihydroindol-2-one (108 mg, 0.5 mmol), TBTU (193 mg, 0 .60 mmol), and triethylamine (152 mg, 1.5 mmol) were stirred together in dichloromethane (3 mL) overnight. Dichloromethane (4 mL) and water (5 mL) were added and the precipitated solid was filtered and washed with water and diethyl ether to give 100 mg of product.

(Example 535)
6- (3-Fluorophenyl) -N-{[2- (4-fluorophenyl) -1,3-oxazol-4-yl] methyl} nicotinamide

６−（３−フルオロフェニル）ニコチン酸（１０９ｍｇ、０．５ｍｍｏｌ）、１−［２−（４−フルオロフェニル）−１，３−オキサゾール−４−イル］メタンアミン（９６．１ｍｇ、０．５ｍｍｏｌ）、ＴＢＴＵ（１９３ｍｇ、０．６０ｍｍｏｌ）、およびトリエチルアミン（１５２ｍｇ、１．５ｍｍｏｌ）を、ジクロロメタン（３ｍＬ）中で終夜一緒に撹拌した。ジクロロメタン（４ｍＬ）および水（５ｍＬ）を加え、沈殿した固体を濾過し、水およびジエチルエーテルで洗浄して、１００ｍｇの生成物を得た。

6- (3-Fluorophenyl) nicotinic acid (109 mg, 0.5 mmol), 1- [2- (4-fluorophenyl) -1,3-oxazol-4-yl] methanamine (96.1 mg, 0.5 mmol) , TBTU (193 mg, 0.60 mmol), and triethylamine (152 mg, 1.5 mmol) were stirred together in dichloromethane (3 mL) overnight. Dichloromethane (4 mL) and water (5 mL) were added and the precipitated solid was filtered and washed with water and diethyl ether to give 100 mg of product.

(Example 542)
6- (3,5-Difluorophenyl) -N- (3,4-dihydro-2H-chromen-3-ylmethyl) nicotinamide

６−（３，５−ジフルオロフェニル）ニコチン酸（４９．０ｍｇ、０．２１７ｍｍｏｌ）、１−（３，４−ジヒドロ−２Ｈ−クロメン−３−イル）メタンアミン（４３．３ｍｇ、０．２１７ｍｍｏｌ）、ＨＡＴＵ（９８．５ｍｇ、０．２５９ｍｍｏｌ）、およびジイソプロピルアミン（２１４ｍｇ、１．６６ｍｍｏｌ）を、アセトニトリル（２ｍＬ）中に混合し、終夜振盪した。反応液を濃縮し、逆相ＨＰＬＣ方法（Ｅ）によって精製した。

6- (3,5-difluorophenyl) nicotinic acid (49.0 mg, 0.217 mmol), 1- (3,4-dihydro-2H-chromen-3-yl) methanamine (43.3 mg, 0.217 mmol), HATU (98.5 mg, 0.259 mmol) and diisopropylamine (214 mg, 1.66 mmol) were mixed in acetonitrile (2 mL) and shaken overnight. The reaction was concentrated and purified by reverse phase HPLC method (E).

(Example 562)
Trans-N-1- (3-Cyano-6-methylpyridin-2-yl) -4-hydroxypyrrolidin-3-yl] -6- (3-fluorophenyl) nicotinamide

バイアルに、トランス−６−（３−フルオロフェニル）−Ｎ−［４−ヒドロキシピロリジン−３−イル］ニコチンアミド（４０ｍｇ、０．１２ｍｍｏｌ）、２−クロロ−６−メチル−ニコチノニトリル（２７．２ｍｇ、０．１８ｍｍｏｌ）、ｎ−ブタノール、水、およびトリエチルアミン（各０．３ｍＬ）を加えた。反応混合物を終夜９０℃に加熱し、次いで室温に冷却し、蒸発にかけた。残渣をＨＰＬＣ方法（Ｅ）によって精製して、所望の生成物のトランス−Ｎ−１−（３−シアノ−６−メチルピリジン−２−イル）−４−ヒドロキシピロリジン−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（４０ｍｇ、８１％）を得た。

In a vial, trans-6- (3-fluorophenyl) -N- [4-hydroxypyrrolidin-3-yl] nicotinamide (40 mg, 0.12 mmol), 2-chloro-6-methyl-nicotinonitrile (27. 2 mg, 0.18 mmol), n-butanol, water, and triethylamine (0.3 mL each) were added. The reaction mixture was heated to 90 ° C. overnight, then cooled to room temperature and evaporated. The residue was purified by HPLC method (E) to give the desired product trans-N-1- (3-cyano-6-methylpyridin-2-yl) -4-hydroxypyrrolidin-3-yl] -6- (3-Fluorophenyl) nicotinamide (40 mg, 81%) was obtained.

(Example 563)
Trans-N-1- (3-Cyano-4,6-dimethylpyridin-2-yl) -4-hydroxypyrrolidin-3-yl] -6- (3-fluorophenyl) nicotinamide

この実施例は、トランス−６−（３−フルオロフェニル）−Ｎ−［４−ヒドロキシピロリジン−３−イル］ニコチンアミド（４０ｍｇ、０．１２ｍｍｏｌ）および２−クロロ−４，６−ジメチル−ニコチノニトリル（２９．０ｍｇ、０．１８ｍｍｏｌ）を使用し、実施例５６２と同様にして調製した。生成物は、ＨＰＬＣ方法（Ｅ）によって精製した。

This example shows trans-6- (3-fluorophenyl) -N- [4-hydroxypyrrolidin-3-yl] nicotinamide (40 mg, 0.12 mmol) and 2-chloro-4,6-dimethyl-nicotino. Prepared as in Example 562 using nitrile (29.0 mg, 0.18 mmol). The product was purified by HPLC method (E).

(Example 564)
Trans-1- (2-ethylimidazo [1,2-b] pyridazin-6-yl) -4-hydroxypyrrolidin-3-yl] -6- (3-fluorophenyl) nicotinamide

この実施例は、トランス−６−（３−フルオロフェニル）−Ｎ−［４−ヒドロキシピロリジン−３−イル］ニコチンアミド（４０ｍｇ、０．１２ｍｍｏｌ）および６−クロロ−２−エチル−イミダゾ［１，２−ｂ］ピリダジン（２９．６ｍｇ、０．１８ｍｍｏｌ）を使用し、実施例５６２と同様にして調製した。生成物は、ＨＰＬＣ方法（Ｅ）によって精製した。

This example includes trans-6- (3-fluorophenyl) -N- [4-hydroxypyrrolidin-3-yl] nicotinamide (40 mg, 0.12 mmol) and 6-chloro-2-ethyl-imidazo [1, 2-b] Pyridazine (29.6 mg, 0.18 mmol) was used and prepared as in Example 562. The product was purified by HPLC method (E).

(Example 567)
6- (3,5-Difluorophenyl) -N- (3,4-dimethoxybenzyl) nicotinamide

この実施例は、６−（３，５−ジフルオロフェニル）ニコチン酸（５４ｍｇ、０．２３ｍｍｏｌ）と３，４−ジメトキシ−ベンジルアミン（３８．０ｍｇ、０．２３ｍｍｏｌ）から、ＰＳ−カルボジイミドを使用して、上記一般方法に記載のとおりに調製した。生成物は、ＨＰＬＣ方法（Ｅ）によって精製した。

This example uses PS-carbodiimide from 6- (3,5-difluorophenyl) nicotinic acid (54 mg, 0.23 mmol) and 3,4-dimethoxy-benzylamine (38.0 mg, 0.23 mmol). And prepared as described in the general method above. The product was purified by HPLC method (E).

(Example 568)
6- (3,5-Difluorophenyl) -N-[(2-oxo-2,3-dihydro-1H-indol-3-yl) methyl] nicotinamide

この実施例は、６−（３，５−ジフルオロフェニル）ニコチン酸（５４ｍｇ、０．２３ｍｍｏｌ）および３−アミノメチル−１，３−ジヒドロ−インドール−２−オン（４４．０ｍｇ、０．２３ｍｍｏｌ）を出発材料として用い、ＨＡＴＵを使用して実施例５４２のように調製した。生成物は、ＨＰＬＣ方法（Ｅ）によって精製した。

This example includes 6- (3,5-difluorophenyl) nicotinic acid (54 mg, 0.23 mmol) and 3-aminomethyl-1,3-dihydro-indol-2-one (44.0 mg, 0.23 mmol) Was prepared as in Example 542 using HATU. The product was purified by HPLC method (E).

(Example 569)
6- (3,5-Difluorophenyl) -N- (3-propoxypropyl) nicotinamide

この実施例は、６−（３，５−ジフルオロフェニル）ニコチン酸（５４ｍｇ、０．２３ｍｍｏｌ）および３−プロポキシ−プロピルアミン（２７．０ｍｇ、０．２３ｍｍｏｌ）を使用し、ＰＳ−カルボジイミドを用いて一般法に記載のとおりに調製した。生成物は、ＨＰＬＣ方法（Ｅ）によって精製した。

This example uses 6- (3,5-difluorophenyl) nicotinic acid (54 mg, 0.23 mmol) and 3-propoxy-propylamine (27.0 mg, 0.23 mmol) with PS-carbodiimide. Prepared as described in General Methods. The product was purified by HPLC method (E).

(Example 570)
6- (3,5-Difluorophenyl) -N-[(1-pyridin-2-ylpiperidin-3-yl) methyl] nicotinamide

この実施例は、６−（３，５−ジフルオロフェニル）ニコチン酸（５４ｍｇ、０．２３ｍｍｏｌ）および３，４，５，６−テトラヒドロ−２Ｈ−［１，２’］ビピリジニル−３−イル）−メチルアミン（６８．０ｍｇ、０．２３ｍｍｏｌ）を出発材料として用い、ＨＡＴＵを使用して実施例５４２のように調製した。生成物は、ＨＰＬＣ方法（Ｅ）によって精製した。

This example shows 6- (3,5-difluorophenyl) nicotinic acid (54 mg, 0.23 mmol) and 3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-3-yl)- Prepared as in Example 542 using HATU with methylamine (68.0 mg, 0.23 mmol) as the starting material. The product was purified by HPLC method (E).

(Example 571)
6- (3,5-Difluorophenyl) -N- {4-[(methylamino) sulfonyl] benzyl} nicotinamide

この実施例は、６−（３，５−ジフルオロフェニル）ニコチン酸（５４ｍｇ、０．２３ｍｍｏｌ）および４−アミノメチル−Ｎ−メチル−ベンゼンスルホンアミド（７１．０ｍｇ、０．３６ｍｍｏｌ）を出発材料として用い、ＰＳ−カルボジイミドを使用して、一般法のセクションに記載のとおりに調製した。残渣を、ジクロロメタン／メタノール／アンモニア（９５：５：０．５）を溶離液とするシリカゲルでのフラッシュクロマトグラフィーによって精製して、６−（３，５−ジフルオロフェニル）−Ｎ−｛４［（メチルアミノ）スルホニル］ベンジル｝ニコチンアミドを得た。

This example uses 6- (3,5-difluorophenyl) nicotinic acid (54 mg, 0.23 mmol) and 4-aminomethyl-N-methyl-benzenesulfonamide (71.0 mg, 0.36 mmol) as starting materials. Used and prepared as described in the General Methods section using PS-carbodiimide. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / ammonia (95: 5: 0.5) to give 6- (3,5-difluorophenyl) -N- {4 [( Methylamino) sulfonyl] benzyl} nicotinamide was obtained.

(Examples 572 and 573)
N-[(3R) -3,4-dihydro-2H-chromen-3-ylmethyl)]-6- (3-fluorophenyl) nicotinamide and N-[(3S) -3,4-dihydro-2H-chromene -3-ylmethyl)]-6- (3-fluorophenyl) nicotinamide

表題化合物のラセミ体を、実施例５４２と似たようにして調製し、次いでＡＤ−Ｈカラム、３０×２５０ｍｍ、流量７０ｍＬ／分、イソプロパノールに２ｍｇ／ｍＬで溶解させたサンプル、５０％ＥｔＯＨ／ＣＯ_２の定組成溶離液を使用して精製した。２つのピークをＣｈｉｒａｌ Ｔｅｃｈｎｏｌｏｇｉｅｓ ＡＤ−Ｈカラム、溶離液５０％ＥｔＯＨ／ＣＯ_２で分析した。
ピーク１、保持時間２．２分は、２８０ｎＭで負のＣＤスペクトルを示した。
ピーク２、保持時間２．５分は、２８０ｎＭで正のＣＤスペクトルを示した。

The racemate of the title compound was prepared as in Example 542, then AD-H column, 30 × 250 mm, flow rate 70 mL / min, sample dissolved in isopropanol at 2 mg / mL, 50% EtOH / CO Purified using ₂ isocratic eluents. Two peaks were analyzed by Chiral Technologies AD-H column, eluent 50% EtOH / CO _2.
Peak 1, retention time 2.2 minutes showed a negative CD spectrum at 280 nM.
Peak 2, retention time 2.5 minutes showed a positive CD spectrum at 280 nM.

(Example 578)
6- (3-Fluorophenyl) -N- (2- (methylamino) ethyl) nicotinamide hydrochloride

ｔｅｒｔ−ブチル２−（６−（３−フルオロフェニル）ニコチンアミド）エチル（メチル）カルバメート（０．２４ｇ、０．６４３ｍｍｏｌ）を１，４−ジオキサン（２ｍＬ）に溶解させ、４Ｍ ＨＣｌジオキサン溶液を加えた（２ｍＬ）。反応混合物を１８時間撹拌した。得られる固体を濾過によって除去し、Ｅｔ_２Ｏ（１０ｍＬ）で洗浄し、風乾した。生成物が収率９３％（０．１８５ｇ、０．５９７ｍｍｏｌ）で得られた。

tert-Butyl 2- (6- (3-fluorophenyl) nicotinamide) ethyl (methyl) carbamate (0.24 g, 0.643 mmol) was dissolved in 1,4-dioxane (2 mL) and 4M HCl dioxane solution was added. (2 mL). The reaction mixture was stirred for 18 hours. The resulting solid was removed by filtration, washed with Et ₂ O (10 mL) and air dried. The product was obtained in 93% yield (0.185 g, 0.597 mmol).

(Example 579)
N- (cyclopropylmethyl) -6- (3-fluorophenyl) nicotinamide

６−（３−フルオロフェニル）ニコチン酸（０．１５ｇ、０．６９１ｍｍｏｌ）を３ｍＬのＤＣＭに溶解させた。この撹拌溶液に、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（０．１４６ｇ、０．７６０ｍｍｏｌ）および１−ヒドロキシ−７−アザベンゾトリアゾール（０．０９４ｇ、０．６９１ｍｍｏｌ）を加えた後、アミノメチルシクロプロパン（０．０４９ｇ、０．６９１ｍｍｏｌ）を加えた。室温で１８時間撹拌した後、水（３ｍＬ）を加え、相を分離した。有機相を真空中で蒸発にかけ、生成物を、ＤＣＭ〜ＤＣＭ／ＭｅＯＨ ８５／１５の勾配を使用するフラッシュカラムクロマトグラフィーに続いて、ＤＣＭ〜ＤＣＭ／ＭｅＯＨ １０／９０の勾配を使用するフラッシュカラムクロマトグラフィーによって精製した。凍結乾燥後に表題化合物を得た（０．０５１ｇ、０．１８９ｍｍｏｌ、収率２７％）。

6- (3-Fluorophenyl) nicotinic acid (0.15 g, 0.691 mmol) was dissolved in 3 mL DCM. To this stirred solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.146 g, 0.760 mmol) and 1-hydroxy-7-azabenzotriazole (0.094 g, 0.691 mmol). Later, aminomethylcyclopropane (0.049 g, 0.691 mmol) was added. After stirring at room temperature for 18 hours, water (3 mL) was added and the phases were separated. The organic phase is evaporated in vacuo and the product is subjected to flash column chromatography using a gradient of DCM to DCM / MeOH 85/15 followed by flash column chromatography using a gradient of DCM to DCM / MeOH 10/90. Purified by chromatography. The title compound was obtained after lyophilization (0.051 g, 0.189 mmol, 27% yield).

  Examples 574-577 and 580-582 were prepared similarly.

(Example 583)
6- (3-Fluorophenyl) -N- (2- (2-isopropoxyethylamino) ethyl) nicotinamide

ベンジル２−（６−（３−フルオロフェニル）ニコチンアミド）エチル（２−イソプロポキシエチル）カルバメート（６７ｍｇ、０．１４０ｍｍｏｌ）および１０％パラジウム担持活性炭（１４．８７ｍｇ、０．１４０ｍｍｏｌ）のエタノール（３ｍＬ）懸濁液を、水素中にて室温で１８時間撹拌した。反応混合物を濾過し、濾液を真空中で濃縮して、４５ｍｇの淡黄色の粘着性固体を得た。この材料を、フラッシュクロマトグラフィー（１〜２％の７Ｍ ＮＨ_３ ＭｅＯＨ溶液を含有するＥｔＯＡｃ）によって精製して、２９．９ｍｇの淡黄色の固体（０．０８２ｍｍｏｌ、収率５９％）を得た。

Ethanol (3 mL) of benzyl 2- (6- (3-fluorophenyl) nicotinamido) ethyl (2-isopropoxyethyl) carbamate (67 mg, 0.140 mmol) and 10% palladium on activated carbon (14.87 mg, 0.140 mmol) ) The suspension was stirred in hydrogen at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 45 mg of a pale yellow sticky solid. This material was purified by flash chromatography (EtOAc containing 1-2% 7M NH ₃ MeOH solution) to give 29.9 mg of a light yellow solid (0.082 mmol, 59% yield).

(Example 584)
N-[(3-Endo) -8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide

ｔｅｒｔ−ブチル（３−エンド）−３−（｛［６−（３−フルオロフェニル）ピリジン−３−イル］カルボニル｝アミノ）−８−アザビシクロ［３．２．１］オクタン−８−カルボキシレート（２２０ｍｇ、０．５１７ｍｍｏｌ）を、ＨＣｌの無水メタノール溶液（１Ｎ、３０ｍＬ）に溶解させ、５０℃で３時間撹拌した。混合物を濃縮し、残渣を、Ｉｓｏｌｕｔｅ ＳＣＸ−２（登録商標）イオン交換樹脂で精製して、Ｎ−［（３−エンド）−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（１４０ｍｇ）を得た。

tert-butyl (3-endo) -3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino) -8-azabicyclo [3.2.1] octane-8-carboxylate ( 220 mg, 0.517 mmol) was dissolved in a solution of HCl in anhydrous methanol (1N, 30 mL) and stirred at 50 ° C. for 3 hours. The mixture was concentrated and the residue was purified on Isolute SCX-2® ion exchange resin to give N-[(3-endo) -8-azabicyclo [3.2.1] oct-3-yl]- 6- (3-Fluorophenyl) nicotinamide (140 mg) was obtained.

(Example 585)
6- (3-Fluorophenyl) -N-[(3-endo) -8-propyl-8-azabicyclo [3.2.1] oct-3-yl] nicotinamide

Ｎ−［（３−エンド）−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（１４５ｍｇ、０．４４６ｍｍｏｌ）のイソプロピルアルコール（１５ｍＬ）溶液に、１−ヨードプロパン（１４６ｍｇ、０．８６２ｍｍｏｌ）および炭酸カリウム（１９８ｍｇ、１．４４ｍｍｏｌ）を加え、混合物を７５℃で１６時間加熱した。溶媒を蒸発させ、残渣を酢酸エチル（２０ｍＬ）と水（５ｍＬ）とに分配した。有機層を分離し、無水ＭｇＳＯ_４で乾燥させ、濾過し、蒸発にかけて、オフホワイトの固体を得た。

N-[(3-endo) -8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide (145 mg, 0.446 mmol) in isopropyl alcohol (15 mL) To was added 1-iodopropane (146 mg, 0.862 mmol) and potassium carbonate (198 mg, 1.44 mmol) and the mixture was heated at 75 ° C. for 16 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and evaporated to give an off-white solid.

(Example 586)
tert-Butyl (3-endo) -3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino) -8-azabicyclo [3.2.1] octane-8-carboxylate

この実施例は、６−（３−フルオロフェニル）ニコチン酸（４８０ｍｇ、２．２１ｍｍｏｌ）と（１Ｓ，３Ｒ，５Ｒ）−３−アミノ−８−アザ−ビシクロ［３．２．１］オクタン−８−カルボン酸ｔｅｒｔ−ブチルエステル（５００ｍｇ、２．２１ｍｍｏｌ）から、一般法で概略を述べたとおりに調製して、ｔｅｒｔ−ブチル（３−エンド）−３−（｛［６−（３−フルオロフェニル）ピリジン−３−イル］カルボニル｝アミノ）−８−アザビシクロ［３．２．１］オクタン−８−カルボキシレートを白色の固体（２７０ｍｇ）として得た。

This example shows 6- (3-fluorophenyl) nicotinic acid (480 mg, 2.21 mmol) and (1S, 3R, 5R) -3-amino-8-aza-bicyclo [3.2.1] octane-8. Prepared from the carboxylic acid tert-butyl ester (500 mg, 2.21 mmol) as outlined in the general method to give tert-butyl (3-endo) -3-({[6- (3-fluorophenyl ) Pyridin-3-yl] carbonyl} amino) -8-azabicyclo [3.2.1] octane-8-carboxylate was obtained as a white solid (270 mg).

(Example 587)
N-[(3-exo) -8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide

ｔｅｒｔ−ブチル（３−エキソ）−３−（｛［６−（３−フルオロフェニル）ピリジン−３−イル］カルボニル｝アミノ）−８−アザビシクロ［３．２．１］オクタン−８−カルボキシレート（５５０ｍｇ、１．２９ｍｍｏｌ）を、ＨＣｌの無水メタノール溶液（１Ｎ、５０ｍＬ）に溶解させ、反応混合物を５０℃で３時間撹拌した。混合物を濃縮し、残渣をＩｓｏｌｕｔｅ ＳＣＸ−２（登録商標）イオン交換樹脂で精製して、Ｎ−［（３−エキソ）−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（３３０ｍｇ）を得た。

tert-Butyl (3-exo) -3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino) -8-azabicyclo [3.2.1] octane-8-carboxylate ( 550 mg, 1.29 mmol) was dissolved in HCl in anhydrous methanol (1N, 50 mL) and the reaction mixture was stirred at 50 ° C. for 3 h. The mixture was concentrated and the residue was purified on Isolute SCX-2® ion exchange resin to give N-[(3-exo) -8-azabicyclo [3.2.1] oct-3-yl] -6. -(3-Fluorophenyl) nicotinamide (330 mg) was obtained.

(Example 588)
tert-Butyl (3-exo) -3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino) -8-azabicyclo [3.2.1] octane-8-carboxylate

この実施例は、６−（３−フルオロフェニル）ニコチン酸（４８０ｍｇ、２．２１ｍｍｏｌ）と（１Ｓ，３Ｓ，５Ｒ）−３−アミノ−８−アザ−ビシクロ［３．２．１］オクタン−８−カルボン酸ｔｅｒｔ−ブチルエステル（５００ｍｇ、２．２１ｍｍｏｌ）から、一般法のセクションで概略を述べたとおりに調製して、ｔｅｒｔ−ブチル（３−エキソ）−３−（｛［６−（３−フルオロフェニル）ピリジン−３−イル］カルボニル｝アミノ）−８−アザビシクロ［３．２．１］オクタン−８−カルボキシレートを白色の固体（７６０ｍｇ）として得た。

This example includes 6- (3-fluorophenyl) nicotinic acid (480 mg, 2.21 mmol) and (1S, 3S, 5R) -3-amino-8-aza-bicyclo [3.2.1] octane-8. Prepared from the carboxylic acid tert-butyl ester (500 mg, 2.21 mmol) as outlined in the general method section to give tert-butyl (3-exo) -3-({[6- (3- Fluorophenyl) pyridin-3-yl] carbonyl} amino) -8-azabicyclo [3.2.1] octane-8-carboxylate was obtained as a white solid (760 mg).

(Example 589)
6- (3-Fluorophenyl) -N-[(3-exo) -8-propyl-8-azabicyclo [3.2.1] oct-3-yl] nicotinamide

この実施例は、Ｎ−［（３−エキソ）−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（１００ｍｇ、０．３０７ｍｍｏｌ）および１−ヨードプロパン（１２０ｍｇ、０．７０５ｍｍｏｌ）を使用し、実施例５８５と同様にして調製して、６−（３−フルオロフェニル）−Ｎ−［（３−エキソ）−８−プロピル−８−アザビシクロ［３．２．１］オクト−３−イル］ニコチンアミドを得た。

This example includes N-[(3-exo) -8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide (100 mg, 0.307 mmol) and 1 Prepared analogously to Example 585 using iodopropane (120 mg, 0.705 mmol) and 6- (3-fluorophenyl) -N-[(3-exo) -8-propyl-8-azabicyclo [3.2.1] Oct-3-yl] nicotinamide was obtained.

(Example 590)
N-[(3-exo) -8-acetyl-8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide

Ｎ−［（３−エキソ）−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（１００ｍｇ、０．３０７ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、トリエチルアミン（０．０８６ｍＬ、０．６１４ｍｍｏｌ）および塩化アセチル（０．０２４ｍＬ、０．３３８ｍｍｏｌ）を加え、反応混合物を室温で２時間撹拌した。反応液をジクロロメタン（５ｍＬ）で希釈し、水（５ｍＬ）で洗浄した。有機層を分離し、無水ＭｇＳＯ_４で乾燥させ、濾過し、蒸発にかけた。残渣を、ジクロロメタン／メタノール／アンモニア（９５：５：０．５）を溶離液とするシリカゲルでのフラッシュクロマトグラフィーによって精製して、Ｎ−［（３−エキソ）−８−アセチル−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミドを白色の固体（１００ｍｇ）として得た。

To a solution of N-[(3-exo) -8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide (100 mg, 0.307 mmol) in dichloromethane (5 mL). , Triethylamine (0.086 mL, 0.614 mmol) and acetyl chloride (0.024 mL, 0.338 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / ammonia (95: 5: 0.5) to give N-[(3-exo) -8-acetyl-8-azabicyclo [ 3.2.1] Oct-3-yl] -6- (3-fluorophenyl) nicotinamide was obtained as a white solid (100 mg).

(Example 591)
6- (3-Fluorophenyl) -N-[(3-exo) -8- (isopropylsulfonyl) -8-azabicyclo [3.2.1] oct-3-yl] nicotinamide

この実施例は、Ｎ−［（３−エキソ）−８−アザビシクロ［３．２．１］オクト−３−イル］−６−（３−フルオロフェニル）ニコチンアミド（１１３ｍｇ、０．３４７ｍｍｏｌ）と塩化イソプロピルスルホニル（０．０８６ｍＬ、０．７６４ｍｍｏｌ）から調製し、生成物は、ＨＰＬＣによって精製した。

This example consists of N-[(3-exo) -8-azabicyclo [3.2.1] oct-3-yl] -6- (3-fluorophenyl) nicotinamide (113 mg, 0.347 mmol) and chloride. Prepared from isopropylsulfonyl (0.086 mL, 0.764 mmol) and the product was purified by HPLC.

  Further examples 592 and 293 can be prepared as follows.

(Example 592)
tert-Butyl 2- (6- (3-fluorophenyl) nicotinamide) ethyl (methyl) carbamate

ｔｅｒｔ−ブチル２−（６−（３−フルオロフェニル）ニコチンアミド）エチル（メチル）カルバメートは、７０％の収率で、Ｎ−（シクロプロピルメチル）−６−（３−フルオロフェニル）ニコチンアミドと似たように調製した。LRMS: 実測値 374 [M+H], 計算値 374.31 [M+H].

tert-Butyl 2- (6- (3-fluorophenyl) nicotinamido) ethyl (methyl) carbamate was obtained in 70% yield with N- (cyclopropylmethyl) -6- (3-fluorophenyl) nicotinamide. Prepared in a similar manner. LRMS: measured value 374 [M + H], calculated value 374.31 [M + H].

(Example 593)
Benzyl 2- (6- (3-fluorophenyl) nicotinamido) ethyl (2-isopropoxyethyl) carbamate

ベンジル２−アミノエチル（２−イソプロポキシエチル）カルバメート（２６０ｍｇ、０．９２７ｍｍｏｌ）および６−（３−フルオロフェニル）ニコチン酸（３０２ｍｇ、１．３９１ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）溶液に、室温でＥＤＣＩ（２６７ｍｇ、１．３９１ｍｍｏｌ）および１−ヒドロキシ−７−アザベンゾトリアゾール（１５１ｍｇ、１．１１３ｍｍｏｌ）を加え、室温で終夜撹拌した。真空中でＤＭＦの大部分を除去した。粗生成物に水（１０ｍＬ）および１Ｍ ＮａＯＨ（２ｍＬ）を加え、この混合物を１０ｍＬのＥｔＯＡｃで２回抽出した。有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空中で濃縮して、４１０ｍｇの淡黄色の油状物を得た。粗生成物をフラッシュクロマトグラフィー（ヘプタン／ＥｔＯＡｃ ７０：３０）によって精製して、７５ｍｇの無色の油状物を得た。LRMS: 実測値 480 [M+H], 計算値 480.56 [M+H].

To a solution of benzyl 2-aminoethyl (2-isopropoxyethyl) carbamate (260 mg, 0.927 mmol) and 6- (3-fluorophenyl) nicotinic acid (302 mg, 1.391 mmol) in N, N-dimethylformamide (20 mL). EDCI (267 mg, 1.391 mmol) and 1-hydroxy-7-azabenzotriazole (151 mg, 1.113 mmol) were added at room temperature and stirred at room temperature overnight. Most of the DMF was removed in vacuo. To the crude product was added water (10 mL) and 1M NaOH (2 mL) and the mixture was extracted twice with 10 mL EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 410 mg of a pale yellow oil. The crude product was purified by flash chromatography (heptane / EtOAc 70:30) to give 75 mg of a colorless oil. LRMS: measured value 480 [M + H], calculated value 480.56 [M + H].

(Example 594)
(3-exo) -3-({[6- (3-fluorophenyl) -pyridin-3-yl] carbonyl} amino) -N-methyl-8-azabicyclo [3.2.1] octane-8-carboxamide

トリホスゲン（５７ｍｇ、０．１９２ｍｍｏｌ）の無水テトラヒドロフラン（２ｍＬ）撹拌氷冷溶液に、Ｎ−（（１Ｒ，３ｓ，５Ｓ）−８−アザビシクロ［３．２．１］オクタン−３−イル）−６−（３−フルオロフェニル）ニコチンアミド（実施例５８２、１２５ｍｇ、０．３８４ｍｍｏｌ）およびジイソプロピルエチルアミン（０．０７４ｍＬ）の無水テトラヒドロフラン（２ｍＬ）溶液を滴下し、滴下が完了した後、反応混合物を室温で１時間撹拌した。次いで、２．０Ｍのメチルアミンテトラヒドロフラン溶液（０．９６ｍＬ、１．９２１ｍｍｏｌ）を加え、反応混合物を室温で終夜撹拌した。反応混合物をメタノール（５ｍＬ）で希釈し、シリカ（６０〜２００μｍ、約１ｇ）を加え、真空中で溶媒を除去した。吸収された材料を、ジクロロメタン／メタノール溶離液で１００：０〜９８：２体積の勾配をかけて溶離しながらフラッシュシリカで精製すると、表題化合物が油状物として得られ、これが凝固した。この粗生成物をジクロロメタン（２ｍＬ）に溶解させ、ジエチルエーテル（２５ｍＬ）をゆっくりと加えてトリチュレートした。生成した懸濁液を５分間撹拌し、次いで固体を濾別し、ジエチルエーテル（２５ｍＬ）で洗浄し、乾燥させて、ベージュ色の粉末７９ｍｇを得た。
LRMS (m/z): 実測値 383
[M+1]; 計算値 383.2 [M+1].
¹HNMR
(DMSO-d₆): 1.63-1.80 (m, 6H), 1.81-2.05 (m, 2H), 2.55-2.70 (m,
3H), 4.20 (bs, 2H), 4.35-4.51 (m, 1H), 6.40-6.51 (m, 1H), 7.30-7.40 (m, 1H),
7.50-7.60 (m, 1H), 7.79-8.12 (m, 1H), 8.10-8.20 (m, 1H), 8.25-8.35 (m, 1H),
8.45-8.55 (m, 1H), 9.05-9.10 (m, 1H).

To a stirred ice-cooled solution of triphosgene (57 mg, 0.192 mmol) in anhydrous tetrahydrofuran (2 mL) was added N-((1R, 3s, 5S) -8-azabicyclo [3.2.1] octane-3-yl) -6. A solution of (3-fluorophenyl) nicotinamide (Example 582, 125 mg, 0.384 mmol) and diisopropylethylamine (0.074 mL) in anhydrous tetrahydrofuran (2 mL) was added dropwise and after the addition was complete, the reaction mixture was stirred at room temperature for 1 Stir for hours. Then 2.0 M methylamine tetrahydrofuran solution (0.96 mL, 1.921 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methanol (5 mL), silica (60-200 μm, ca. 1 g) was added and the solvent was removed in vacuo. The absorbed material was purified on flash silica eluting with a dichloromethane / methanol eluent with a gradient of 100: 0 to 98: 2 to give the title compound as an oil that solidified. The crude product was dissolved in dichloromethane (2 mL) and triturated with slow addition of diethyl ether (25 mL). The resulting suspension was stirred for 5 minutes, then the solid was filtered off, washed with diethyl ether (25 mL) and dried to give 79 mg of beige powder.
LRMS (m / z): Actual value 383
[M + 1]; calculated 383.2 [M + 1].
¹ HNMR
(DMSO-d ₆ ): 1.63-1.80 (m, 6H), 1.81-2.05 (m, 2H), 2.55-2.70 (m,
3H), 4.20 (bs, 2H), 4.35-4.51 (m, 1H), 6.40-6.51 (m, 1H), 7.30-7.40 (m, 1H),
7.50-7.60 (m, 1H), 7.79-8.12 (m, 1H), 8.10-8.20 (m, 1H), 8.25-8.35 (m, 1H),
8.45-8.55 (m, 1H), 9.05-9.10 (m, 1H).

(Example 595)
(3-exo) -3-({[6- (3-fluorophenyl) -pyridin-3-yl] carbonyl} amino) -N, N-dimethyl-8-azabicyclo [3.2.1] octane-8 -Carboxamide

表題化合物は、メチルアミンの代わりに２Ｍジメチルアミンテトラヒドロフラン溶液（０．９６ｍＬ、１．９２１ｍｍｏｌ）を使用したことを除き、実施例５９４と同様にして調製した。表題化合物は、ジクロロメタン：メタノール溶離液で１００：０〜９６：４体積の勾配をかけて溶離するフラッシュシリカでのクロマトグラフィーによって単離した。表題化合物は、油状物として単離され、それが凝固した。この粗生成物をジクロロメタン（２ｍＬ）に溶解させ、ジエチルエーテル（２５ｍＬ）をゆっくりと加えてトリチュレートした。生成した懸濁液を５分間撹拌し、次いで固体を濾別し、ジエチルエーテル（２５ｍＬ）で洗浄し、乾燥させて、白色の粉末８４ｍｇを得た。
LRMS (m/z): 実測値 397
[M+1]; 計算値 397.46 [M+1].
¹HNMR
(DMSO-d₆): 1.65-1.89 (m, 8H), 2.82 (s, 6H), 4.00-4.09 (bs, 2H),
4.34-4.44 (m, 1H), 7.34-7.44 (m, 1H), 7.52-7.59 (m, 1H), 7.90-8.05 (m, 1H),
8.10-8.19 (m, 1H), 8.25-8.30 (m, 1H), 8.50-8.60 (m, 1H), 9.05-9.10 (m, 1H).

The title compound was prepared as in Example 594 except that 2M dimethylamine tetrahydrofuran solution (0.96 mL, 1.921 mmol) was used instead of methylamine. The title compound was isolated by chromatography on flash silica eluting with a dichloromethane: methanol eluent with a gradient of 100: 0 to 96: 4 volume. The title compound was isolated as an oil that solidified. The crude product was dissolved in dichloromethane (2 mL) and triturated with slow addition of diethyl ether (25 mL). The resulting suspension was stirred for 5 minutes, then the solid was filtered off, washed with diethyl ether (25 mL) and dried to give 84 mg of a white powder.
LRMS (m / z): Measured value 397
[M + 1]; calculated 397.46 [M + 1].
¹ HNMR
(DMSO-d ₆ ): 1.65-1.89 (m, 8H), 2.82 (s, 6H), 4.00-4.09 (bs, 2H),
4.34-4.44 (m, 1H), 7.34-7.44 (m, 1H), 7.52-7.59 (m, 1H), 7.90-8.05 (m, 1H),
8.10-8.19 (m, 1H), 8.25-8.30 (m, 1H), 8.50-8.60 (m, 1H), 9.05-9.10 (m, 1H).

(Example 596)
6- (3-Fluorophenyl) -N- (3-exo) -8-[(4-hydroxypiperidin-1-ylcarbonyl] -8-azabicyclo [3.2.1] octyl-3-yl} nicotinamide

表題化合物は、メチルアミンの代わりに４−ヒドロキシピペリジン（１９４ｍｇ、１．９２１ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液を使用したことを除き、実施例５９４と同様にして調製した。表題化合物は、ジクロロメタン：メタノール溶離液で１００：０〜９０：１０体積の勾配をかけて溶離するフラッシュシリカでのクロマトグラフィーによって単離した。表題化合物は、油状物として単離され、それが凝固した。この粗生成物をジクロロメタン（２ｍＬ）に溶解させ、ジエチルエーテル（２５ｍＬ）をゆっくりと加えてトリチュレートした。生成した懸濁液を５分間撹拌し、次いで固体を濾別し、ジエチルエーテル（２５ｍＬ）で洗浄し、乾燥させて、淡黄色の粉末１０２ｍｇを得た。
LRMS (m/z): 実測値 453
[M+1]; 計算値 453.52 [M+1].
¹HNMR
(DMSO-d₆): 1.20-1.35 (m, 2H), 1.65-1.90 (m, 10), 2.89-3.01 (m, 2H),
3.50-3.69 (m, 3H), 3.95-4.02 (bs, 2H), 4.25-4.42 (m, 1H), 4.70-4.78 (m, 1H),
7.29-7.36 (m, 1H), 7.50-7.60 (m, 1H), 7.91-8.01 (m, 1H), 8.10-8.20 (m, 1H),
8.20-8.30 (m, 1H), 8.46-8.56 (m, 1H), 9.05-9.10 (m, 1H).

The title compound was prepared in the same manner as in Example 594, except that 4-hydroxypiperidine (194 mg, 1.921 mmol) in tetrahydrofuran (1 mL) was used instead of methylamine. The title compound was isolated by chromatography on flash silica eluting with a dichloromethane: methanol eluent with a gradient of 100: 0 to 90:10 volume. The title compound was isolated as an oil that solidified. The crude product was dissolved in dichloromethane (2 mL) and triturated with slow addition of diethyl ether (25 mL). The resulting suspension was stirred for 5 minutes, then the solid was filtered off, washed with diethyl ether (25 mL) and dried to give 102 mg of a pale yellow powder.
LRMS (m / z): Actual value 453
[M + 1]; calculated 453.52 [M + 1].
¹ HNMR
(DMSO-d ₆ ): 1.20-1.35 (m, 2H), 1.65-1.90 (m, 10), 2.89-3.01 (m, 2H),
3.50-3.69 (m, 3H), 3.95-4.02 (bs, 2H), 4.25-4.42 (m, 1H), 4.70-4.78 (m, 1H),
7.29-7.36 (m, 1H), 7.50-7.60 (m, 1H), 7.91-8.01 (m, 1H), 8.10-8.20 (m, 1H),
8.20-8.30 (m, 1H), 8.46-8.56 (m, 1H), 9.05-9.10 (m, 1H).

(Example 597)
(3-exo) -3-({[6- (3-fluorophenyl) -pyridin-3-yl] carbonyl} amino) -N- (2-hydroxyethyl) -8-azabicyclo [3.2.1] Octane-8-carboxamide

表題化合物は、メチルアミンの代わりに２−アミノエタノール（１１７ｍｇ、１．９２１ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液を使用したことを除き、実施例５９４と同様にして調製した。表題化合物は、ジクロロメタン：メタノール溶離液で１００：０〜９０：１０体積の勾配をかけて溶離するフラッシュシリカでのクロマトグラフィーによって単離した。表題化合物は、油状物として単離され、それが凝固した。この粗生成物をジクロロメタン（２ｍＬ）に溶解させ、ジエチルエーテル（２５ｍＬ）をゆっくりと加えてトリチュレートした。得られる懸濁液を５分間撹拌し、次いで固体を濾別し、ジエチルエーテル（２５ｍＬ）で洗浄し、乾燥させて、白色の粉末８７ｍｇを得た。
LRMS (m/z): 実測値 413
[M+1]; 計算値 413.46 [M+1].
¹HNMR
(DMSO-d₆): 1.60-1.75 (m, 6H), 1.85-1.95 (m, 2H), 3.05-3.15 (m, 2H),
3.35-3.46 (m, 2H), 4.18-4.25 (bs, 2H), 4.35-4.42 (m, 1H), 4.62-4.70 (m, 1H),
6.40-6.50 (m, 1H), 7.28-7.35 (m, 1H), 7.50-7.60 (m, 1H), 7.92-8.00 (m, 1H),
8.10-8.17 (m, 1H), 8.22-8.28 (m, 1H), 8.45-8.52 (m, 1H), 9.05-9.10 (m, 1H).

The title compound was prepared in the same manner as in Example 594 except that 2-aminoethanol (117 mg, 1.921 mmol) in tetrahydrofuran (1 mL) was used instead of methylamine. The title compound was isolated by chromatography on flash silica eluting with a dichloromethane: methanol eluent with a gradient of 100: 0 to 90:10 volume. The title compound was isolated as an oil that solidified. The crude product was dissolved in dichloromethane (2 mL) and triturated with slow addition of diethyl ether (25 mL). The resulting suspension was stirred for 5 minutes, then the solid was filtered off, washed with diethyl ether (25 mL) and dried to give 87 mg of a white powder.
LRMS (m / z): Actual value 413
[M + 1]; calculated 413.46 [M + 1].
¹ HNMR
(DMSO-d ₆ ): 1.60-1.75 (m, 6H), 1.85-1.95 (m, 2H), 3.05-3.15 (m, 2H),
3.35-3.46 (m, 2H), 4.18-4.25 (bs, 2H), 4.35-4.42 (m, 1H), 4.62-4.70 (m, 1H),
6.40-6.50 (m, 1H), 7.28-7.35 (m, 1H), 7.50-7.60 (m, 1H), 7.92-8.00 (m, 1H),
8.10-8.17 (m, 1H), 8.22-8.28 (m, 1H), 8.45-8.52 (m, 1H), 9.05-9.10 (m, 1H).

  The following section describes the synthesis of intermediates used in the preparation of the previous examples.

Preparation Example 1
6- (3-Fluorophenyl) nicotinic acid

６−クロロニコチン酸（３７．０ｇ、０．２３５ｍｏｌ）のトルエン溶液に、３−フルオロフェニルボロン酸（３９．５ｇ、０．２８２ｍｏｌ）、Ｋ_２ＣＯ_３（１５０ｇ）の水（７００ｍＬ）溶液、［Ｂｕ_４Ｎ］Ｂｒ（３．５ｇ、０．０１０７ｍｏｌ）、およびＰｄ（ＰＰｈ_３）_４（１２．４ｇ、０．０１０７ｍｏｌ）を加えた。反応混合物を還流させながら２０時間撹拌した。冷却した後、反応混合物を濾過し、２Ｍ ＨＣｌでｐＨ３に酸性化した。形成した沈殿を濾過によって分離し、乾燥させて、６−（３−フルオロフェニル）ニコチン酸（４９．９ｇ）を得た。¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.29 (td, J=8.46, 2.42 Hz, 1 H)
7.50-7.56 (m, 1 H) 7.93 (dd, J=10.47, 2.15 Hz, 1 H) 7.97 (d, J=7.79 Hz, 1 H)
8.11 (d, J=8.06 Hz, 1 H) 8.30 (dd, J=8.32, 2.15 Hz, 1 H) 9.11 (d, J=1.88 Hz, 1
H), 13.48 (bs, 1H).

To a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene, a solution of 3-fluorophenylboronic acid (39.5 g, 0.282 mol), K ₂ CO ₃ (150 g) in water (700 mL), [ Bu ₄ N] Br (3.5 g, 0.0107 mol) and Pd (PPh ₃ ) ₄ (12.4 g, 0.0107 mol) were added. The reaction mixture was stirred at reflux for 20 hours. After cooling, the reaction mixture was filtered and acidified to pH 3 with 2M HCl. The formed precipitate was separated by filtration and dried to give 6- (3-fluorophenyl) nicotinic acid (49.9 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.29 (td, J = 8.46, 2.42 Hz, 1 H)
7.50-7.56 (m, 1 H) 7.93 (dd, J = 10.47, 2.15 Hz, 1 H) 7.97 (d, J = 7.79 Hz, 1 H)
8.11 (d, J = 8.06 Hz, 1 H) 8.30 (dd, J = 8.32, 2.15 Hz, 1 H) 9.11 (d, J = 1.88 Hz, 1
H), 13.48 (bs, 1H).

Preparation Example 2
5-Chloro-6- (3-fluorophenyl) nicotinic acid

丸底フラスコに、５，６−ジクロロニコチン酸（５００ｍｇ、２．６０ｍｍｏｌ）、３−フルオロフェニルボロン酸（３６４ｍｇ、２．６０ｍｍｏｌ）、ＤＭＦ（２５ｍＬ）、２Ｍ Ｃｓ_２ＣＯ_３（６ｍＬ）、およびＰｄ（ＰＰｈ_３）_４（３０．１ｍｇ、０．０２６ｍｍｏｌ）を加えた。反応混合物を３時間９０℃に加熱し、次いで室温に冷ました。混合物を酢酸エチル／水で希釈し、層を分離した。有機層をブラインで洗浄し、乾燥させ（ＭｇＳＯ_４）、蒸発にかけて固体を得、これをクロマトグラフィー（シリカ、ＤＣＭ／ＭｅＯＨ）によって精製して、所望の生成物である５−クロロ−６−（３−フルオロフェニル）ニコチン酸（６２３ｍｇ、９５％）を得た。LRMS実測値 252 [M+H], 計算値 252.02 [M+H]

In a round bottom flask, 5,6-dichloronicotinic acid (500 mg, 2.60 mmol), 3-fluorophenylboronic acid (364 mg, 2.60 mmol), DMF (25 mL), 2M Cs ₂ CO ₃ (6 mL), and Pd (PPh ₃ ) ₄ (30.1 mg, 0.026 mmol) was added. The reaction mixture was heated to 90 ° C. for 3 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate / water and the layers were separated. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give a solid that was purified by chromatography (silica, DCM / MeOH) to give the desired product 5-chloro-6- ( 3-Fluorophenyl) nicotinic acid (623 mg, 95%) was obtained. LRMS measured value 252 [M + H], calculated value 252.02 [M + H]

Preparation Example 3
6- (3,5-Difluorophenyl) -nicotinic acid

ステップＡ：ｔｅｒｔ−ブチル６−ブロモニコチネートの調製 ２−ブロモ−５−ピリジンカルボン酸（１０．０ｇ、４９ｍｍｏｌ）のＤＣＭ（５００ｍＬ）溶液を含有する丸底フラスコに、臭化オキサリル（７．４ｍＬ）および５滴のＤＭＦを加えた。若干の気体を放出させた後、反応混合物を還流温度で約６時間撹拌し、次いで室温に冷却し、ヘプタン（１００ｍＬ）を加えた後、混合物を濃縮した。次いで混合物をＴＨＦ（４００ｍＬ）に懸濁させ、０℃に冷却した。ｔ−ＢｕＯＫ（５．８ｇ、５２ｍｍｏｌ）を加え、反応液を室温に温め、２時間撹拌した。混合物をＥｔＯＡｃ中に注ぎ、１Ｎ ＮａＯＨ、水、およびブラインで洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をＢｉｏｔａｇｅ（商標）４０Ｓでのシリカゲルクロマトグラフィー（ヘプタン ＥｔＯＡｃ ０〜８０％、３Ｌ）によって精製して、表題化合物４．２ｇ（３６％）を白色の固体として得た。¹H NMR (400MHz, DMSO-d₆) δ ppm 8.78-8.86 (1 H, m), 8.14 (1 H, dd,
J=8.4, 2.4 Hz), 7.81 (1 H, d, J=8.4 Hz), 1.56 (9 H, s).

Step A: Preparation of tert-butyl 6-bromonicotinate To a round bottom flask containing a solution of 2-bromo-5-pyridinecarboxylic acid (10.0 g, 49 mmol) in DCM (500 mL) was added oxalyl bromide (7.4 mL). ) And 5 drops of DMF. After releasing some gas, the reaction mixture was stirred at reflux temperature for about 6 hours, then cooled to room temperature, heptane (100 mL) was added and the mixture was concentrated. The mixture was then suspended in THF (400 mL) and cooled to 0 ° C. t-BuOK (5.8 g, 52 mmol) was added and the reaction was warmed to room temperature and stirred for 2 hours. The mixture was poured into EtOAc, washed with 1N NaOH, water, and brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography on Biotage ™ 40S (heptane EtOAc 0-80%, 3 L) to give 4.2 g (36%) of the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 8.78-8.86 (1 H, m), 8.14 (1 H, dd,
J = 8.4, 2.4 Hz), 7.81 (1 H, d, J = 8.4 Hz), 1.56 (9 H, s).

Step B: Preparation of tert-butyl 6- (3,5-difluorophenyl) nicotinate In a round bottom flask, 3,5-difluorophenylboronic acid (1.84 g, 11.6 mmol), palladium tetrakis (triphenylphosphine) ( 89.5 mg, 0.08 mmol), and tert- butyl 6-bromo-nicotinate (2.0 g, 7.75 mmol) was added and the mixture was evacuated three times with _{N 2.} The solid was dissolved in DMF (50 mL) and 2M cesium carbonate (11 mL) was added. The resulting mixture was heated to about 90 ° C. until no starting bromide material was found by HPLC. The mixture was cooled to room temperature and then poured into a separatory funnel before adding EtOAc and water (1 × 200 mL). The layers were separated and the organic extract was washed with brine (1 × 200 mL), dried over MgSO ₄ , filtered and concentrated to give an orange oil. The crude mixture was purified by silica gel column chromatography on Biotage ™ (silica, 2-10% EtOAc heptane solution, 2.5 L) to afford 2.1 g (93%) of the title compound as a white solid. Obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.10-9.14 (1 H, m), 8.29-8.35 (1 H,
m), 8.20-8.25 (1 H, m), 7.90 (2 H, dd, J = 9.0, 1.5 Hz), 7.42 (1 H, s), 1.59 (9
H, s).

Step C: Preparation of 6- (3,5-difluoro-phenyl) -nicotinic acid To DCM (80 mL) containing tert-butyl 6- (3,5-difluorophenyl) nicotinate was added trifluoroacetic acid (20 mL). It was. After stirring at room temperature overnight, toluene was added (100 mL) and the solvent was removed to give the crude product as a white powder. The solid was recrystallized from MeOH to give 1.269 g (74%) of the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 9.16 (1 H, d, J = 1.7 Hz), 8.37 (1 H,
dd, J = 8.2, 2.0 Hz), 8.23 (1 H, d, J = 8.2 Hz), 7.86-7.95 (2 H, m), 7.36-7.47 (1
H, m).

Preparation Example 4
6- (5-Fluoro-2-hydroxyphenyl) nicotinic acid

ステップＡ：メチル６−（５−フルオロ−２−ヒドロキシフェニル）ニコチネート １，４−ジオキサン（１２ｍＬ）と水（３ｍＬ）の脱気した混合物に、（５−フルオロ−２−ヒドロキシフェニル）ボロン酸（０．７８１ｇ、５．０ｍｍｏｌ）、６−クロロニコチン酸メチル（０．８６ｇ、５．０ｍｍｏｌ）、炭酸カリウム（２．０８ｇ、１５．０ｍｍｏｌ）、およびテトラキス（トリフェニルホスフィン）パラジウム（０）（０．２９ｇ、０．０５ｍｍｏｌ）を加え、得られる混合物を８０℃で２時間撹拌した。この時間経過後、追加のテトラキス（トリフェニルホスフィン）パラジウム（０）（０．２９ｇ、０．０５ｍｍｏｌ）を加え、８０℃でさらに３時間加熱を続けた。次いで混合物を室温で終夜撹拌した。真空中で溶媒を蒸発させ、残渣を酢酸エチル（５０ｍＬ）に懸濁させた。懸濁液をＡｒｂｏｃｅｌ（商標）充填物で濾過し、濾液を真空中で濃縮した。得られる残渣を酢酸エチル（１００ｍＬ）に溶解させ、飽和炭酸ナトリウム水溶液（３×１００ｍＬ）で洗浄した。水性洗液を合わせ、酢酸エチル（３×５０ｍＬ）で抽出した。酢酸エチル層を合わせ、無水ＭｇＳＯ_４で乾燥させ、真空中で濃縮して固体を得、これをジクロロメタン／ヘプタンから再結晶させて、表題化合物を黄色の固体（０．７１ｇ）（５７％）として得た。¹H NMR (400 MHz, CDCl₃) δ ppm 9.14 (1 H, s), 8.46 - 8.40 (1 H, m), 7.91 - 7.86 (1 H, m), 7.53
- 7.46 (1 H, m), 7.11 - 7.03 (1 H, m), 7.02 - 6. 96 (1
H, m), 3.99 (3 H, s). LRMS: AP m/z 248 [M+H]⁺.

Step A: Methyl 6- (5-fluoro-2-hydroxyphenyl) nicotinate 1,4-dioxane (12 mL) and water (3 mL) were degassed with (5-fluoro-2-hydroxyphenyl) boronic acid ( 0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol), and tetrakis (triphenylphosphine) palladium (0) (0 .29 g, 0.05 mmol) was added and the resulting mixture was stirred at 80 ° C. for 2 h. After this time, additional tetrakis (triphenylphosphine) palladium (0) (0.29 g, 0.05 mmol) was added and heating was continued at 80 ° C. for an additional 3 hours. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was suspended in ethyl acetate (50 mL). The suspension was filtered through an Arbocel ™ charge and the filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium carbonate (3 × 100 mL). The aqueous washes were combined and extracted with ethyl acetate (3 × 50 mL). The ethyl acetate layers were combined, dried over anhydrous MgSO ₄ and concentrated in vacuo to give a solid which was recrystallized from dichloromethane / heptane to give the title compound as a yellow solid (0.71 g) (57%) Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.14 (1 H, s), 8.46-8.40 (1 H, m), 7.91-7.86 (1 H, m), 7.53
-7.46 (1 H, m), 7.11-7.03 (1 H, m), 7.02-6. 96 (1
H, m), 3.99 (3 H, s). LRMS: AP m / z 248 [M + H] ⁺ .

Step B: Methyl 6- (5-fluoro-2-hydroxyphenyl) nicotinate 6- (5-fluoro-2-hydroxyphenyl) nicotinate (1.47 g, 6.0 mmol) was dissolved in MeOH (35 mL) and 0 Cooled to ° C. Lithium hydroxide (0.71 g, 30.0 mmol) was then added and the mixture was stirred at 0 ° C. for 0.5 h. The mixture was then warmed to room temperature. Additional lithium hydroxide (0.43 g, 18.0 mmol) was added and the reaction mixture was stirred at room temperature for 72 hours. The mixture was then concentrated in vacuo and the resulting yellow solid was dissolved in water (150 mL). 1N aqueous HCl was added to acidify the solution to pH 1 and the resulting precipitate was filtered and washed with 0.5 M aqueous HCl to give the title compound as a yellow powder (1.15 g) (72%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (1 H, s), 8.42-8.28 (2 H, m) 7.94-7.84 (1 H, m), 7.26
-7.15 (1H, m), 7.02-6.92 (1 H, m) .LRMS: ES m / z 234
[M + H] ⁺ .

Preparation Example 5
Trans-tert-butyl 3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino) -4-hydroxypyrrolidine-1-carboxylate

６−（３−フルオロフェニル）ニコチン酸（３９１ｍｇ、１．８ｍｍｏｌ）をＤＭＦ（１０ｍＬ）に溶かした０℃の溶液に、ＨＡＴＵ（７５３ｍｇ、１．９８ｍｍｏｌ）およびＤＩＰＥＡ（０．４７ｍＬ、２．０７ｍｍｏｌ）を加えた。１５分後、トランス−ｔｅｒｔ−ブチル３−アミノ−４−ヒドロキシピロリジン−１−カルボキシレートを加え、反応混合物を室温で５時間撹拌した。真空中で溶媒を除去し、残渣を酢酸エチルおよび水で希釈した。層を分離し、有機層をブラインで洗浄し、乾燥させ（ＭｇＳＯ_４）、蒸発にかけて、油状物を得た。クロマトグラフィー（シリカ、６５％の酢酸エチル：ヘキサン）によって精製すると、所望の生成物のトランス−ｔｅｒｔ−ブチル−３−（｛［６−（３−フルオロフェニル）ピリジン−３−イル］カルボニル｝アミノ）−４−ヒドロキシピロリジン−１−カルボキシレート（４２０ｍｇ、５８％）が得られた。LC/MS (M+H) = 実測値401.9, 計算値402.18.

To a 0 ° C. solution of 6- (3-fluorophenyl) nicotinic acid (391 mg, 1.8 mmol) in DMF (10 mL) was added HATU (753 mg, 1.98 mmol) and DIPEA (0.47 mL, 2.07 mmol). Was added. After 15 minutes, trans-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate was added and the reaction mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give an oil. Purification by chromatography (silica, 65% ethyl acetate: hexane) yields the desired product trans-tert-butyl-3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino. ) -4-hydroxypyrrolidine-1-carboxylate (420 mg, 58%) was obtained. LC / MS (M + H) = measured 401.9, calculated 402.18.

Preparation Example 6
Trans-6- (3-Fluorophenyl) -N- [4-hydroxypyrrolidin-3-yl] nicotinamide

トランス−ｔｅｒｔ−ブチル３−（｛［６−（３−フルオロフェニル）ピリジン−３−イル］カルボニル｝アミノ）−４−ヒドロキシピロリジン−１−カルボキシレート（５００ｍｇ、１．２４ｍｍｏｌ）のジオキサン溶液に、４Ｎ ＨＣｌジオキサン溶液（１０ｍＬ）を加えた。反応液を室温で約４時間撹拌し、次いでエーテルで希釈して、白色の固体を得、これを濾過し、収集して、所望の生成物のトランス−６−（３−フルオロフェニル）−Ｎ−［４−ヒドロキシピロリジン−３−イル］ニコチンアミドを塩酸塩（３９０ｍｇ、９２％）として得た。LC/MS (M+H) = 実測値301.9, 計算値302.13.

To a dioxane solution of trans-tert-butyl 3-({[6- (3-fluorophenyl) pyridin-3-yl] carbonyl} amino) -4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.24 mmol), 4N HCl dioxane solution (10 mL) was added. The reaction is stirred at room temperature for about 4 hours and then diluted with ether to give a white solid which is filtered and collected to give the desired product trans-6- (3-fluorophenyl) -N. -[4-Hydroxypyrrolidin-3-yl] nicotinamide was obtained as the hydrochloride salt (390 mg, 92%). LC / MS (M + H) = measured 301.9, calculated 302.13.

Preparation Example 8
tert-Butyl 2- (2-isopropoxyethylamino) ethylcarbamate

２−イソプロポキシエタンアミン（８２９ｍｇ、８．０３ｍｍｏｌ）およびＫＩ（１３３ｍｇ、０．８０３ｍｍｏｌ）の５ｍｌのＮ，Ｎ−ジメチルホルムアミド懸濁液に、ｔｅｒｔ−ブチル２−ブロモエチルカルバメート（９００ｍｇ、４．０２ｍｍｏｌ）を５ｍｌのＮ，Ｎ−ジメチルホルムアミドに溶かした溶液を、不活性雰囲気中にて室温で滴下した。反応混合物を４５℃で７２時間撹拌した。水（２０ｍＬ）を加え、反応混合物をＥｔ_２Ｏ（２０ｍＬ）で２回抽出した。有機層を合わせて２０ｍＬの０．５Ｍ ＨＣｌおよびブラインで洗浄した。酸性の水層を合わせて飽和Ｎａ_２ＣＯ_３で中和し、２０ｍＬのＥｔ_２Ｏで抽出した。得られる有機相をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空中で濃縮して、４００ｍｇの無色の油状物（１．６２４ｍｍｏｌ、収率４０％）を得た。
¹H
NMR (CDCl₃, 400 MHz) δ ppm 1.152-1.167
(m, 6H) 1.447 (s, 9H) 3.343-3.602 (m, 7H) 4.132-4.145 (m, 2H) 4.795-4.885 (br
m, 1H) 5.100-5.150 (br m, 1H)

To a suspension of 2-isopropoxyethanamine (829 mg, 8.03 mmol) and KI (133 mg, 0.803 mmol) in 5 ml of N, N-dimethylformamide was added tert-butyl 2-bromoethylcarbamate (900 mg, 4.02 mmol). ) In 5 ml N, N-dimethylformamide was added dropwise at room temperature in an inert atmosphere. The reaction mixture was stirred at 45 ° C. for 72 hours. Water (20 mL) was added and the reaction mixture was extracted twice with Et ₂ O (20 mL). The organic layers were combined and washed with 20 mL of 0.5 M HCl and brine. The acidic aqueous layers were combined, neutralized with saturated Na ₂ CO ₃ and extracted with 20 mL Et ₂ O. The resulting organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 400 mg of a colorless oil (1.624 mmol, 40% yield).
¹ H
NMR (CDCl ₃ , 400 MHz) δ ppm 1.152-1.167
(m, 6H) 1.447 (s, 9H) 3.343-3.602 (m, 7H) 4.132-4.145 (m, 2H) 4.795-4.885 (br
m, 1H) 5.100-5.150 (br m, 1H)

Preparation Example 9
Benzyl 2-tert-butoxycarbonylaminoethyl (2-isopropoxyethyl) carbamate

ｔｅｒｔ−ブチル２−（２−イソプロポキシエチルアミノ）エチルカルバメート（４００ｍｇ、１．６２４ｍｍｏｌ）およびトリエチルアミン（０．２７２ｍｌ、１．９４８ｍｍｏｌ）のジクロロメタン（１０ｍＬ）撹拌溶液に、クロロギ酸ベンジル（３０５ｍｇ、１．７８６ｍｍｏｌ）を滴下した。反応混合物を１８時間撹拌し、その後ＴＬＣ（ヘプタン／ＥｔＯＡｃ １：１＋１％ＮＨ３ ＭｅＯＨ溶液）によって、新たな化合物に完全に変換されたことが示された。反応混合物をＥｔＯＡｃ（３０ｍＬ）で希釈し、水（３０ｍＬ）およびブライン（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空中で濃縮して、４６０ｍｇの無色の油状物（１．２０９ｍｍｏｌ、収率７５％）を得た。
¹H
NMR (CDCl₃, 400 MHz) δ ppm 1.122-1.200
(m, 6H) 1.428 (s, 9H) 3.316-3.613 (m, 9H) 5.134-5.143 (m, 2H) 5.350-5.400 (m,
1H) 7.322-7.366 (m, 5H).

To a stirred solution of tert-butyl 2- (2-isopropoxyethylamino) ethylcarbamate (400 mg, 1.624 mmol) and triethylamine (0.272 ml, 1.948 mmol) in dichloromethane (10 mL) was added benzyl chloroformate (305 mg, 1. 786 mmol) was added dropwise. The reaction mixture was stirred for 18 hours, after which time TLC (heptane / EtOAc 1: 1 + 1% NH 3 MeOH solution) showed complete conversion to the new compound. The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL) and brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give 460 mg of a colorless oil (1.209 mmol, Yield 75%).
¹ H
NMR (CDCl ₃ , 400 MHz) δ ppm 1.122-1.200
(m, 6H) 1.428 (s, 9H) 3.316-3.613 (m, 9H) 5.134-5.143 (m, 2H) 5.350-5.400 (m,
1H) 7.322-7.366 (m, 5H).

Preparation Example 10
Benzyl 2-aminoethyl (2-isopropoxyethyl) carbamate

ベンジル２−ｔｅｒｔ−ブトキシカルボニルアミノエチル（２−イソプロポキシエチル）カルバメート（４６０ｍｇ、１．２０９ｍｍｏｌ）のトリフルオロ酢酸（２０ｍＬ、２６０ｍｍｏｌ）溶液を温度で２時間撹拌し、引き続いて真空中で濃縮して、４６０ｍｇの油状物（１．６４１ｍｍｏｌ、収率１３６％、残留トリフルオロ酢酸を依然として含有する）を得た。この生成物をそれ以上精製せずに使用した。
LRMS: 実測値 281
[M+H], 計算値 281.37 [M+H].

A solution of benzyl 2-tert-butoxycarbonylaminoethyl (2-isopropoxyethyl) carbamate (460 mg, 1.209 mmol) in trifluoroacetic acid (20 mL, 260 mmol) is stirred at temperature for 2 h and subsequently concentrated in vacuo. 460 mg of an oil (1.641 mmol, 136% yield, still containing residual trifluoroacetic acid) was obtained. This product was used without further purification.
LRMS: Actual value 281
[M + H], calculated value 281.37 [M + H].

Preparation Example 12
1- (4-Chlorobenzyl) -3-aminopyrrolidin-2-one Step 1. Preparation of 2,4-dibromo-butyryl chloride

化合物γ−ブチロラクトン（２００ｇ、２．３２ｍｏｌ）とＰＢｒ_３（４ｍＬ）の混合物を１００℃で加熱し、Ｂｒ_２（１００ｍＬ）を、反応混合物の表面より下にゆっくりと加え、その間反応温度は１１０〜１１５℃に保った。ＤＭＦ（０．２ｍＬ）を５０℃で加え、次いでＳＯＣｌ_２（２００ｍＬ）を９０℃で滴下した。撹拌をさらに３時間続けた。混合物を蒸留し、４２〜４４℃（５ｍｍＨｇ）で沸騰する画分を収集して、３２３ｇ（５２．６％）の塩化２，４−ジブロモ−ブチリルを黄色の液体として得た。1H NMR (400 MHz CDCl3) δ ppm 2.49-2.73 (m,
2H), 3.60 (m, 2H), 4.83 (m, 1H).

A mixture of compound γ-butyrolactone (200 g, 2.32 mol) and PBr ₃ (4 mL) is heated at 100 ° C. and Br ₂ (100 mL) is slowly added below the surface of the reaction mixture, while the reaction temperature is 110-110. Maintained at 115 ° C. DMF (0.2 mL) was added at 50 ° C. and then SOCl ₂ (200 mL) was added dropwise at 90 ° C. Stirring was continued for an additional 3 hours. The mixture was distilled and the fraction boiling at 42-44 ° C. (5 mm Hg) was collected to give 323 g (52.6%) of 2,4-dibromo-butyryl chloride as a yellow liquid. 1H NMR (400 MHz CDCl3) δ ppm 2.49-2.73 (m,
2H), 3.60 (m, 2H), 4.83 (m, 1H).

  Step 2. Preparation of N- (4-chlorobenzyl) -2,4-dibromobutanamide

４−クロロベンジルアミン（２５０ｇ、１．７７ｍｏｌ）およびＥｔ_３Ｎ（２３２ｇ、２．２９ｍｏｌ）の無水ジクロロメタン（３Ｌ）撹拌溶液に、塩化２，４−ジブロモ−ブチリル（５５２ｇ、２．１３ｍｏｌ）を０℃で滴下した。２時間後、ＴＬＣ（ＥｔＯＡｃ／石油エーテル＝１：１）によって、材料が完全に消費されたことが示された。混合物を水（１Ｌ×２）で洗浄し、有機層を分離し、Ｎａ_２ＳＯ_４で乾燥させ、蒸発にかけて、５０８ｇ（７８％）のＮ−（４−クロロベンジル）−２，４−ジブロモブタンアミドを褐色のシロップとして得、これをそれ以上精製せずに次のステップに使用した。
¹H NMR
(400 MHz CDCl₃) δ ppm 2.40-2.80 (m, 2H),
3.58 (m, 2H), 4.38-4.61 (m, 3H), 7.20-7.40 (m, 4H).

To a stirred solution of 4-chlorobenzylamine (250 g, 1.77 mol) and Et ₃ N (232 g, 2.29 mol) in anhydrous dichloromethane (3 L) was added 2,4-dibromo-butyryl chloride (552 g, 2.13 mol) to 0. It was dripped at ° C. After 2 hours, TLC (EtOAc / petroleum ether = 1: 1) showed that the material was completely consumed. The mixture was washed with water (1 L × 2), the organic layer was separated, dried over Na ₂ SO ₄ and evaporated to 508 g (78%) N- (4-chlorobenzyl) -2,4-dibromobutane. The amide was obtained as a brown syrup that was used in the next step without further purification.
¹ H NMR
(400 MHz CDCl ₃ ) δ ppm 2.40-2.80 (m, 2H),
3.58 (m, 2H), 4.38-4.61 (m, 3H), 7.20-7.40 (m, 4H).

  Step 3.1 Preparation of 1- (4-Chlorobenzyl) -3-bromopyrrolidin-2-one

ＮａＨ（８４ｇ、２．１ｍｏｌ）の無水ＴＨＦ（４Ｌ）撹拌懸濁液に、Ｎ−（４−クロロベンジル）−２，４−ジブロモブタンアミド（５０５ｇ、１．３８ｍｏｌ）の無水ＴＨＦ（１５００ｍＬ）溶液を０℃で滴下した。加えた後、反応混合物を室温に温め、終夜撹拌した。ＴＬＣ（ＥｔＯＡｃ／石油エーテル＝１：５）によって、材料が完全に消費されたことが示された。反応混合物を濾過し、濾液を真空中で濃縮して、未精製の１−（４−クロロベンジル）−３−ブロモピロリジン−２−オン（２６０ｇ、６６％）を黒色の液体として得、これをそれ以上精製せずに次のステップで使用した。

To a stirred suspension of NaH (84 g, 2.1 mol) in anhydrous THF (4 L), N- (4-chlorobenzyl) -2,4-dibromobutanamide (505 g, 1.38 mol) in anhydrous THF (1500 mL) Was added dropwise at 0 ° C. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. TLC (EtOAc / petroleum ether = 1: 5) showed that the material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give crude 1- (4-chlorobenzyl) -3-bromopyrrolidin-2-one (260 g, 66%) as a black liquid which Used in the next step without further purification.

  Step 4.1 Preparation of 1- (4-Chlorobenzyl) -3-aminopyrrolidin-2-one

１−（４−クロロベンジル）−３−ブロモピロリジン−２−オン（２６０ｇ、０．９４ｍｏｌ）のアセトニトリル（２Ｌ）溶液に、アンモニア（１２５０ｍＬ）を加えた。混合物を室温で終夜撹拌した。ＴＬＣ（ＭｅＯＨ／ＣＨ_２Ｃｌ_２＝１：１５）によって、材料が完全に消費されたことが示され、混合物を真空中で蒸発にかけた。粗生成物（１８０ｇ、９２％）をカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２）によって精製して、未精製の１−（４−クロロベンジル）−３−アミノピロリジン−２−オン（１０８ｇ、５５％）を褐色の液体として得た。この未精製化合物のアミノ基をｔｅｒｔ−ブチルカルバメート誘導体として保護し、カラムクロマトグラフィーを使用して精製した。この純粋な材料を、４Ｍ ＨＣｌ ＭｅＯＨ溶液を用いて脱保護して、対応する塩を得、次いでこれを塩基性化して、１−（４−クロロベンジル）−３−アミノピロリジン−２−オン（５０ｇ、２５．６％）を褐色の油状物として得た。
LRMS: 実測値 225
[M+H], 計算値 225.69 [M+H].

To a solution of 1- (4-chlorobenzyl) -3-bromopyrrolidin-2-one (260 g, 0.94 mol) in acetonitrile (2 L) was added ammonia (1250 mL). The mixture was stirred at room temperature overnight. TLC (MeOH / CH ₂ Cl ₂ = 1: 15) showed that the material was completely consumed and the mixture was evaporated in vacuo. The crude product (180 g, 92%) was purified by column chromatography (CH ₂ Cl ₂ ) to give crude 1- (4-chlorobenzyl) -3-aminopyrrolidin-2-one (108 g, 55%). Was obtained as a brown liquid. The amino group of this crude compound was protected as a tert-butyl carbamate derivative and purified using column chromatography. This pure material was deprotected using 4M HCl MeOH solution to give the corresponding salt, which was then basified to give 1- (4-chlorobenzyl) -3-aminopyrrolidin-2-one ( 50 g, 25.6%) was obtained as a brown oil.
LRMS: Actual value 225
[M + H], calculated 225.69 [M + H].

Preparation Example 13
3-Amino-1- (4-methyl-benzyl) -pyrrolidin-2-one Step 1.2-Preparation of tert-butoxycarbonylamino-4-methylsulfanyl-butyric acid

メチオニン（１６１ｇ、１．０８１ｍｏｌ）のジオキサン（２．５Ｌ）および水（２．５Ｌ）懸濁液に、ＮａＯＨ（７８ｇ、１．９５ｍｏｌ）の水（５００ｍＬ）溶液を加えた。次いで、反応混合物に二炭酸ジ−ｔｅｒｔ−ブチル（３０６ｇ、１．４ｍｏｌ）を０℃で滴下した。反応混合物を室温で１２時間撹拌した。ジオキサンを蒸発させ、残渣を酢酸エチル（１×１Ｌ）で希釈した。有機相を分離し、無水Ｎａ_２ＳＯ_４で乾燥させ、真空中で蒸発にかけた。粗生成物を、１０％のＥｔＯＡｃヘキサン溶液を溶離液とするシリカゲル（１００〜２００メッシュ）でのカラムクロマトグラフィーによって精製して、化合物を無色の液体（２１５ｇ、８０％）として得た。

To a suspension of methionine (161 g, 1.081 mol) in dioxane (2.5 L) and water (2.5 L) was added a solution of NaOH (78 g, 1.95 mol) in water (500 mL). Then, di-tert-butyl dicarbonate (306 g, 1.4 mol) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at room temperature for 12 hours. Dioxane was evaporated and the residue was diluted with ethyl acetate (1 × 1 L). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (100-200 mesh) eluting with 10% EtOAc in hexanes to give the compound as a colorless liquid (215 g, 80%).

  Step 2: Preparation of [1- (4-Methyl-benzylcarbamoyl) -3-methylsulfanyl-propyl] -carbamic acid tert-butyl ester

窒素雰囲気中にある０℃に冷却（氷浴）した２−ｔｅｒｔ−ブトキシカルボニルアミノ−４−メチルスルファニル−酪酸（２１２ｇ、０．８５１ｍｏｌ）の無水ＤＣＭ（４Ｌ）撹拌溶液に、無水ＨＯＢＴ（１５０ｇ、１．１１ｍｏｌ）、ＥＤＣＩ（２１３ｇ、１．１１ｍｏｌ）、Ｎ，Ｎジ−イソプロピルエチルアミン（２２０ｇ、１．７０２ｍｏｌ）、および４−メチルベンジルアミン（１０８ｇ、０．８９４ｍｏｌ）を加えた。反応混合物を室温で１８時間撹拌した。氷冷１Ｎ ＨＣｌ（水溶液）（１×２５０ｍｌ）で反応を失活させた。有機相を分離し、飽和炭酸水素ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥させた。粗生成物をＣＨ_２Ｃｌ_２：エーテル（２：８）で結晶化して、生成物を白色の固体（１８０ｇ、６０％）として得た。

To a stirred solution of 2-tert-butoxycarbonylamino-4-methylsulfanyl-butyric acid (212 g, 0.851 mol) in anhydrous nitrogen (4 L) in a nitrogen atmosphere cooled to 0 ° C. (ice bath) was added anhydrous HOBT (150 g, 1.11 mol), EDCI (213 g, 1.11 mol), N, N di-isopropylethylamine (220 g, 1.702 mol), and 4-methylbenzylamine (108 g, 0.894 mol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with ice-cold 1N HCl (aq) (1 × 250 ml). The organic phase was separated and washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate. The crude product was crystallized with CH ₂ Cl ₂ : ether (2: 8) to give the product as a white solid (180 g, 60%).

  Step 3: Preparation of [1- (4-Methyl-benzyl) -2-oxo-pyrrolidin-3-yl] -carbamic acid tert-butyl ester

［１−（４−メチル−ベンジルカルバモイル）−３−メチルスルファニル−プロピル］−カルバミン酸ｔｅｒｔ−ブチルエステル（１７５ｇ、０．４９７ｍｏｌ）をヨードメタン（６９０ｇ、４．９４ｍｏｌ）に溶解させ、溶液を窒素雰囲気中で４８時間撹拌した。減圧下での蒸留によってヨードメタンを除去して、スルホニウム塩を黄色の固体（２１３ｇ、０．４３３ｍｏｌ、８８％）として得た。これを窒素中にて無水ＴＨＦ（４Ｌ）中、０℃（氷浴）で撹拌し、リチウムビス（トリメチルシリル）アミド（１．０Ｍ ＴＨＦ溶液、４３１ｍＬ、０．４３１ｍｏｌ）を滴下した。反応混合物をこの温度で３時間撹拌した。次いで反応混合物を飽和塩化アンモニウム水溶液（２００ｍＬ）で失活させ、減圧下で大部分のＴＨＦを除去した。残留する溶媒をＮａＨＣＯ_３水溶液とＣＨ_２Ｃｌ_２とに分配した。水層をＣＨ_２Ｃｌ_２でさらに抽出した。有機相を合わせて硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。粗生成物をＣＨ_２Ｃｌ_２：エーテル（２：８）から結晶させて、生成物を白色の固体（９２ｇ、６０％）として得た。

[1- (4-Methyl-benzylcarbamoyl) -3-methylsulfanyl-propyl] -carbamic acid tert-butyl ester (175 g, 0.497 mol) was dissolved in iodomethane (690 g, 4.94 mol) and the solution was nitrogen atmosphere For 48 hours. The iodomethane was removed by distillation under reduced pressure to give the sulfonium salt as a yellow solid (213 g, 0.433 mol, 88%). This was stirred at 0 ° C. (ice bath) in anhydrous THF (4 L) in nitrogen, and lithium bis (trimethylsilyl) amide (1.0 M THF solution, 431 mL, 0.431 mol) was added dropwise. The reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride (200 mL) and most of the THF was removed under reduced pressure. The remaining solvent was partitioned between aqueous NaHCO ₃ and CH ₂ Cl ₂ . The aqueous layer was further extracted with CH ₂ Cl ₂ . The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was crystallized from CH ₂ Cl ₂ : ether (2: 8) to give the product as a white solid (92 g, 60%).

  Step 4: Preparation of 3-amino-1- (4-methyl-benzyl) -pyrrolidin-2-one hydrochloride

［１−（４−メチル−ベンジル）−２−オキソ−ピロリジン−３−イル］−カルバミン酸ｔｅｒｔ−ブチルエステル（９０ｇ、０．２９６ｍｏｌ）の無水ＤＣＭ（１．５Ｌ）溶液上に、０℃（氷浴）で１時間、無水ＨＣｌガスを通した。溶液を真空中で濃縮して、所望の化合物を塩酸塩（５７ｇ、８０％）として得た。MS: 実測値 205.4 [M+H], 計算値 205.3 [M+H].

On a solution of [1- (4-methyl-benzyl) -2-oxo-pyrrolidin-3-yl] -carbamic acid tert-butyl ester (90 g, 0.296 mol) in anhydrous DCM (1.5 L) at 0 ° C. Anhydrous HCl gas was passed through in an ice bath for 1 hour. The solution was concentrated in vacuo to give the desired compound as the hydrochloride salt (57 g, 80%). MS: Found 205.4 [M + H], Calculated 205.3 [M + H].

Preparation Example 14
[1- (6-Methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) piperidin-3-yl] methylamine trihydrochloride Step 1.3-[( Preparation of (Dimethylamino) methylene] -1-methylpiperidin-4-one

１−メチルピペリジン−４−オン（４８ｇ、０．４２５ｍｏｌ）およびＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（６１ｇ、０．５１３ｍｏｌ）を含有するｏ−キシロール（３５０ｍＬ）およびＫ_２ＣＯ_３（２７ｇ）を、沸点６４〜６５℃の揮発性物質画分（主にメタノール）を継続的に除去しながら、揮発性物質画分の沸点が上昇し始めるまで（約２．５時間）（１４０〜１５０℃）で加熱した。次いで、混合物である反応液を室温に冷却し、濾過し、蒸発にかけて、表題化合物を赤色の油状物（５０．４ｇ）として得た。

O-Xylol (350 mL) containing 1-methylpiperidin-4-one (48 g, 0.425 mol) and N, N-dimethylformamide dimethyl acetal (61 g, 0.513 mol) and K ₂ CO ₃ (27 g), While continuously removing the volatile fraction (mainly methanol) having a boiling point of 64 to 65 ° C., until the boiling point of the volatile fraction starts to rise (about 2.5 hours) (140 to 150 ° C.) Heated. The mixture reaction was then cooled to room temperature, filtered and evaporated to give the title compound as a red oil (50.4 g).

  Step 2. Preparation of tert-butyl [(1-benzylpiperidin-3-yl) methyl] carbamate

［（１−ベンジルピペリジン−３−イル）メチル］アミン（３７７．３ｇ、１．８５ｍｏｌ）、二炭酸ジ−ｔｅｒｔ−ブチル（４０３．２ｇ、１．８５ｍｏｌ）、およびトリエチルアミン（２５７．３ｍｌ、１．８５ｍｏｌ）のアセトニトリル（４００ｍＬ）溶液を、室温で１２時間撹拌した。次いで混合物を蒸発にかけ、残渣をヘキサン（５００ｍＬ）と共に撹拌した。生成した沈殿を濾過し、ヘキサンで洗浄し、乾燥させて、表題化合物（５２８．４ｇ）を得た。

[(1-Benzylpiperidin-3-yl) methyl] amine (377.3 g, 1.85 mol), di-tert-butyl dicarbonate (403.2 g, 1.85 mol), and triethylamine (257.3 ml, 1. 85 mol) in acetonitrile (400 mL) was stirred at room temperature for 12 hours. The mixture was then evaporated and the residue was stirred with hexane (500 mL). The resulting precipitate was filtered, washed with hexane and dried to give the title compound (528.4 g).

  Step 3. Preparation of tert-butyl (piperidin-3-ylmethyl) carbamate

ｔｅｒｔ−ブチル［（１−ベンジルピペリジン−３−イル）メチル］カルバメート（２５１ｇ）を、５％Ｐｄ／Ｃ（５０ｇ）の存在下、メタノール（１Ｌ）中にて１０時間水素化した（８０ｐｓｉ）。混合物をＣｅｌｉｔｅで濾過し、濾液を蒸発にかけ、残渣をヘキサンと共に撹拌した。生成した沈殿を濾過し、ヘキサンで洗浄し、乾燥させて、表題化合物（１５６．５ｇ）を得た。

Tert-butyl [(1-benzylpiperidin-3-yl) methyl] carbamate (251 g) was hydrogenated (80 psi) in methanol (1 L) in the presence of 5% Pd / C (50 g) for 10 hours. The mixture was filtered through Celite, the filtrate was evaporated and the residue was stirred with hexane. The resulting precipitate was filtered, washed with hexane and dried to give the title compound (156.5 g).

  Step 4. Preparation of tert-butyl ({1- [amino (imino) methyl] piperidin-3-yl} methyl) carbamate

ｔｅｒｔ−ブチル（ピペリジン−３−イルメチル）カルバメート（３２４．０ｇ、１．５ｍｏｌ）、１Ｈ−ピラゾール−１−カルボキシイミドアミド塩酸塩（２２１．８ｇ、１．５ｍｏｌ）、およびジイソプロピルエチルアミン（２６３．２ｍＬ、１．５ｍｏｌ）のＤＭＦ（７００ｍＬ）溶液を、室温で４８時間撹拌した。次いで、混合物を乾燥するまで蒸発にかけ、残渣をエーテルと共に撹拌し、生成した沈殿を濾過し、エーテルで洗浄し、乾燥させて、表題化合物（４３５．９ｇ）を得た。

tert-Butyl (piperidin-3-ylmethyl) carbamate (324.0 g, 1.5 mol), 1H-pyrazole-1-carboximidamide hydrochloride (221.8 g, 1.5 mol), and diisopropylethylamine (263.2 mL, 1.5 mol) in DMF (700 mL) was stirred at room temperature for 48 hours. The mixture was then evaporated to dryness, the residue was stirred with ether and the resulting precipitate was filtered, washed with ether and dried to give the title compound (435.9 g).

  Step 5. Preparation of tert-butyl {[1- (6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) piperidin-3-yl] methyl} carbamate

ｔｅｒｔ−ブチル（｛１−［アミノ（イミノ）メチル］ピペリジン−３−イル｝メチル）カルバメート（５０ｇ、０．１７ｍｏｌ）、３−［（ジメチルアミノ）メチレン］−１−メチルピペリジン−４−オン（２９ｇ、０．１７ｍｏｌ）、およびナトリウムメトキシド（１３．５ｇ、０．２５ｍｏｌ）の無水エタノール（５００ｍＬ）懸濁液を、８時間還流させた。反応混合物を蒸発にかけ、残渣を水と共に撹拌した。生成した沈殿を濾過し、水およびエーテルで洗浄し、乾燥させて、表題化合物（４６．５ｇ）を得た。

tert-butyl ({1- [amino (imino) methyl] piperidin-3-yl} methyl) carbamate (50 g, 0.17 mol), 3-[(dimethylamino) methylene] -1-methylpiperidin-4-one ( 29 g, 0.17 mol) and sodium methoxide (13.5 g, 0.25 mol) in absolute ethanol (500 mL) was refluxed for 8 hours. The reaction mixture was evaporated and the residue was stirred with water. The resulting precipitate was filtered, washed with water and ether and dried to give the title compound (46.5 g).

  Step 6. Preparation of [1- (6-Methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) piperidin-3-yl] methylamine trihydrochloride

メタノールの溶液（５０ｍＬ）および４Ｎ ＨＣｌジオキサン溶液（２５０ｍＬ）に、ｔｅｒｔ−ブチル（｛１−［アミノ（イミノ）メチル］ピペリジン−３−イル｝メチル）カルバメート（４６．５ｇ、０．１７７ｍｏｌ）を加えた。混合物を室温で１２時間撹拌し、蒸発にかけ、残渣をクロマトグラフィーによって精製して、表題化合物（２３．１ｇ）を得た。
¹H NMR
(DMSO-d₆, 400MHz) δ ppm 1.20 - 1.44
(m, 2H), 1.68 - 1.82 (m, 3H), 2.65 - 2.89 (m, 6H), 2.96 - 3.20 (m, 1H), 3.21 -
3.40 (m, 1H), 3.31 - 3.46 (m, 1H), 3.55 - 3.68 (m, 1H), 4.05 - 4.12 (m, 1H),
4.22 - 4.35 (m, 1H), 4.37 - 4.45 (m, 1H), 4.51 - 4.59 (m, 1H), 8.15 (b, 2H),
8.23 (s, 1H). LCMS [M+H]⁺ = 371.

To a solution of methanol (50 mL) and 4N HCl in dioxane (250 mL) was added tert-butyl ({1- [amino (imino) methyl] piperidin-3-yl} methyl) carbamate (46.5 g, 0.177 mol). It was. The mixture was stirred at room temperature for 12 hours, evaporated and the residue purified by chromatography to give the title compound (23.1 g).
¹ H NMR
(DMSO-d ₆ , 400MHz) δ ppm 1.20-1.44
(m, 2H), 1.68-1.82 (m, 3H), 2.65-2.89 (m, 6H), 2.96-3.20 (m, 1H), 3.21-
3.40 (m, 1H), 3.31-3.46 (m, 1H), 3.55-3.68 (m, 1H), 4.05-4.12 (m, 1H),
4.22-4.35 (m, 1H), 4.37-4.45 (m, 1H), 4.51-4.59 (m, 1H), 8.15 (b, 2H),
8.23 (s, 1H). LCMS [M + H] ⁺ = 371.

Preparation Example 15
2- [5- (2-Methoxy-phenyl)-[1,3,4] oxadiazol-2-yl] -ethylamine Step 1. Preparation of N-Boc-β-alanine-methyl ester

β−アラニンメチルエステル塩酸塩（７１０ｇ、５．０７ｍｏｌ）のメタノール（２０００ｍＬ）溶液に、蒸留したばかりのトリエチルアミン（７５０ｍＬ、５４５ｇ、５．４ｍｏｌ）を、激しく撹拌しながら加えた。トリエチルアミンを加える間、反応混合物を氷浴で冷却した。次いで、混合物に二炭酸ジ−ｔｅｒｔ−ブチルを少量ずつ加え（５０ｇずつ、合計１１１０ｇ、５．１ｍｏｌ）、反応液を１２時間撹拌した。混合物を減圧下で濃縮して体積を半分にし、クロロホルム（５００ｍＬ）で洗浄しながら、溶液から塩酸トリエチルアンモニウムを濾過した。濾液をクロロホルム（２０００ｍＬ）で希釈し、混合物を水（２５００ｍＬ）、次いで１０％ｗ／ｗクエン酸水溶液（２５００ｍＬ）で洗浄した。有機層を真空中で蒸発にかけて、Ｎ−Ｂｏｃ−β−アラニン−メチルエステルを透明な無色の油状物（１０３０ｇ）として得た。この生成物をそれ以上精製せずに次の段階で使用した。

To a solution of β-alanine methyl ester hydrochloride (710 g, 5.07 mol) in methanol (2000 mL), freshly distilled triethylamine (750 mL, 545 g, 5.4 mol) was added with vigorous stirring. The reaction mixture was cooled with an ice bath while the triethylamine was added. Subsequently, di-tert-butyl dicarbonate was added to the mixture little by little (50 g, 1110 g in total, 5.1 mol), and the reaction solution was stirred for 12 hours. The mixture was concentrated under reduced pressure to halve the volume and triethylammonium hydrochloride was filtered from the solution while washing with chloroform (500 mL). The filtrate was diluted with chloroform (2000 mL) and the mixture was washed with water (2500 mL) followed by 10% w / w aqueous citric acid (2500 mL). The organic layer was evaporated in vacuo to give N-Boc-β-alanine-methyl ester as a clear colorless oil (1030 g). This product was used in the next step without further purification.

  Step 2. Preparation of N-Boc-β-alanine hydrazide

Ｎ−Ｂｏｃ−β−アラニン−メチルエステル（１０３０ｇ）を含有するイソプロパノール（１５００ｍＬ）に、ヒドラジン水和物（１０００ｍＬ、１０３２ｇ、２０ｍｏｌ）を加え、混合物を還流冷却器で１６時間還流させた。反応混合物を蒸発乾燥させ、クロロホルム（２０００ｍＬ）に溶解し直した。次いで溶液を水（２０００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させ、蒸発乾燥させた。生成物をジエチルエーテル（２０００ｍＬ）から結晶化し、濾過し、真空乾燥して、Ｎ−Ｂｏｃβ−アラニンヒドラジド（７７１ｇ）を得た。

Hydrazine hydrate (1000 mL, 1032 g, 20 mol) was added to isopropanol (1500 mL) containing N-Boc-β-alanine-methyl ester (1030 g), and the mixture was refluxed with a reflux condenser for 16 hours. The reaction mixture was evaporated to dryness and redissolved in chloroform (2000 mL). The solution was then washed with water (2000 mL), dried over sodium sulfate and evaporated to dryness. The product was crystallized from diethyl ether (2000 mL), filtered and dried in vacuo to give N-Bocβ-alanine hydrazide (771 g).

  Step 3. Preparation of {2- [5- (2-methoxy-phenyl)-[1,3,4] oxadiazol-2-yl] -ethyl} -carbamic acid tert-butyl ester

２−メトキシ安息香酸（３４．６５ｇ、０．２２８ｍｏｌ）、トリフェニルホスフィン（１７９．２ｇ、０．６８４ｍｏｌ）、およびトリエチルアミン（７３．７３ｇ、０．７３ｍｏｌ）の無水アセトニトリル（９００ｍＬ）混合物を、アルゴン雰囲気中で１０〜１５分間撹拌し、０℃に冷却した。無水四塩化炭素（１３９．１ｍＬ）を加え、混合物をこの温度でもう１５分間撹拌した。Ｎ−Ｂｏｃ−β−アラニンヒドラジド（４６．２８ｇ、０．２２８ｍｏｌ）を一度に加え、温度を＜５℃に保ちながら混合物を１５分間撹拌した。氷浴を取り外し、混合物を室温で３時間撹拌した。生成した沈殿を濾過し、アセトニトリル（１０００ｍＬ）で洗浄した。真空中で溶媒を除去し、残渣を酢酸エチル（１００ｍＬ）に溶解し直した。混合物を軽く加熱しながら１５分間撹拌した。残渣を濾別し、酢酸エチルで洗浄した。減圧下で濾液を濃縮し、酢酸エチルを溶離液とするカラムクロマトグラフィーによって精製して、表題化合物を淡黄色の粘稠な油状物として得た。

A mixture of 2-methoxybenzoic acid (34.65 g, 0.228 mol), triphenylphosphine (179.2 g, 0.684 mol), and triethylamine (73.73 g, 0.73 mol) in anhydrous acetonitrile (900 mL) was added to an argon atmosphere. Stir in for 10-15 minutes and cool to 0 ° C. Anhydrous carbon tetrachloride (139.1 mL) was added and the mixture was stirred at this temperature for another 15 minutes. N-Boc-β-alanine hydrazide (46.28 g, 0.228 mol) was added in one portion and the mixture was stirred for 15 minutes while keeping the temperature <5 ° C. The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The resulting precipitate was filtered and washed with acetonitrile (1000 mL). The solvent was removed in vacuo and the residue was redissolved in ethyl acetate (100 mL). The mixture was stirred for 15 minutes with light heating. The residue was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by column chromatography eluting with ethyl acetate to give the title compound as a pale yellow viscous oil.

  Step 4. Preparation of 2- [5- (2-methoxy-phenyl)-[1,3,4] oxadiazol-2-yl] -ethylamine

｛２−［５−（２−メトキシ−フェニル）−［１，３，４］オキサジアゾール−２−イル］−エチル｝−カルバミン酸ｔｅｒｔ−ブチルエステル）を無水塩化メチレン（４００ｍＬ）に溶解させ、氷水浴で冷却した。トリフルオロ酢酸（１４０ｍＬ）を加え、反応混合物を周囲温度で２０時間撹拌した。真空中で溶媒および大部分のトリフルオロ酢酸を除去し、水を加え、得られる混合物をベンゼンで抽出した。水層を炭酸カリウムで飽和させてアルカリ性のｐＨにし、クロロホルム（５００ｍＬ）で３回抽出した。有機相を合わせて無水硫酸ナトリウムで乾燥させ、真空中で濃縮し、クロロホルム−メタノール−トリエチルアミン、１０：１：１を溶離液とするカラムクロマトグラフィーによって精製して、３０．０ｇ（６０％）の表題化合物を遊離塩基として得た。
LCMS (ES): 実測値 220.2
(M+1), 計算値 220.25 [M+1].
¹H NMR
(400 MHz d₆-DMSO) δ ppm 2.92-2.93 (m, 4H),
3.87 (s, 3H), 7.09-7.14 (m, 1H), 7.24-7.27 (m, 1H), 7.56-7.61 (m, 1H),
7.78-7.81 (m, 1H).

{2- [5- (2-methoxy-phenyl)-[1,3,4] oxadiazol-2-yl] -ethyl} -carbamic acid tert-butyl ester) is dissolved in anhydrous methylene chloride (400 mL). Cooled in an ice-water bath. Trifluoroacetic acid (140 mL) was added and the reaction mixture was stirred at ambient temperature for 20 hours. The solvent and most of the trifluoroacetic acid were removed in vacuo, water was added and the resulting mixture was extracted with benzene. The aqueous layer was saturated with potassium carbonate to an alkaline pH and extracted three times with chloroform (500 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography eluting with chloroform-methanol-triethylamine, 10: 1: 1 to give 30.0 g (60%). The title compound was obtained as the free base.
LCMS (ES): Measured 220.2
(M + 1), calculated value 220.25 [M + 1].
¹ H NMR
(400 MHz d ₆ -DMSO) δ ppm 2.92-2.93 (m, 4H),
3.87 (s, 3H), 7.09-7.14 (m, 1H), 7.24-7.27 (m, 1H), 7.56-7.61 (m, 1H),
7.78-7.81 (m, 1H).

Preparation Example 16
2- (2-Aminoethyl) -1-ethyl-N- (2-methoxyethyl) -1H-benzimidazole-5-carboxamide Step 1. Methyl 3-{[N- (tert-butoxycarbonyl) -β-alanyl] amino} -4- (ethylamino) benzoate

３−Ｎ−ｔｅｒｔ−ブチルオキシカルボニルアミノプロピオン酸（４８７．６ｇ、２．５８ｍｏｌ）およびＨＯＢｔ（４８７ｇ、３．６１ｍｏｌ）のＣＨ_２Ｃｌ_２（５Ｌ）混合物に、ＥＤＣ（５６０ｇ、３．６１ｍｏｌ）を加えた。得られる混合物を室温で１時間撹拌した。３−アミノ−４−エチルアミノ安息香酸メチルエステル（Ｂｉｏｏｒｇａｎｉｃ＆Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ、１３（５）、２００５、１５８７〜１５９７の方法に従って調製したもの、５００ｇ、２．５８ｍｏｌ）を加え、混合物を室温で終夜撹拌した。混合物を飽和ＮＨ_４Ｃｌ水溶液（１０Ｌ）およびブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空中で濃縮して、必要な生成物であるメチル３−｛［Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−β−アラニル］アミノ｝−４−（エチルアミノ）ベンゾエート（１２００ｇ、１００％）を灰色の固体として得た。

To a CH ₂ Cl ₂ (5 L) mixture of 3-N-tert-butyloxycarbonylaminopropionic acid (487.6 g, 2.58 mol) and HOBt (487 g, 3.61 mol) was added EDC (560 g, 3.61 mol). added. The resulting mixture was stirred at room temperature for 1 hour. 3-Amino-4-ethylaminobenzoic acid methyl ester (Bioorganic & Medicinal Chemistry, 13 (5), 2005, prepared from 1587-1597, 500 g, 2.58 mol) was added and the mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous NH ₄ Cl (10 L) and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the required product methyl 3-{[N- (tert-butoxycarbonyl). -Β-alanyl] amino} -4- (ethylamino) benzoate (1200 g, 100%) was obtained as a gray solid.

  Step 2. Methyl 2- {2-[(tert-butoxycarbonyl) amino] ethyl} -1-ethyl-1H-benzimidazole-5-carboxylate

メチル３−｛［Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−β−アラニル］アミノ｝−４−（エチルアミノ）ベンゾエート（１０００ｇ、２．７４ｍｏｌ）とＭｅＯＨ（１５Ｌ）の混合物に、ｐａｒａ−トルエンスルホン酸（４７１ｇ、２．７４ｍｏｌ）を加えた。得られる混合物を４時間加熱還流した。真空中で溶媒の大部分を除去し、残渣を飽和Ｎａ_２ＣＯ_３水溶液（４０Ｌ）中に注いだ。得られる混合物を濾過し、フィルターケーキを石油エーテルで洗浄して、メチル２−｛２［（ｔｅｒｔ−ブトキシカルボニル）アミノ］エチル｝−１−エチル−１Ｈ−ベンゾイミダゾール−５−カルボキシレート（７００ｇ、７３．６％）を灰色の固体として得た。

To a mixture of methyl 3-{[N- (tert-butoxycarbonyl) -β-alanyl] amino} -4- (ethylamino) benzoate (1000 g, 2.74 mol) and MeOH (15 L) was added para-toluenesulfonic acid ( 471 g, 2.74 mol) was added. The resulting mixture was heated to reflux for 4 hours. Most of the solvent was removed in vacuo and the residue was poured into saturated aqueous Na ₂ CO ₃ (40 L). The resulting mixture was filtered and the filter cake was washed with petroleum ether to give methyl 2- {2 [(tert-butoxycarbonyl) amino] ethyl} -1-ethyl-1H-benzimidazole-5-carboxylate (700 g, 73.6%) was obtained as a gray solid.

  Step 3. 2- {2-[(tert-Butoxycarbonyl) amino] ethyl} -1-ethyl-1H-benzimidazole-5-carboxylic acid

メチル２−｛２［（ｔｅｒｔ−ブトキシカルボニル）アミノ］エチル｝−１−エチル−１Ｈ−ベンゾイミダゾール−５−カルボキシレート（５００ｇ、１．４４ｍｏｌ）のＭｅＯＨ（７Ｌ）溶液に、ＬｉＯＨ（５１．９ｇ、２．１６ｍｏｌ）の水（３Ｌ）溶液を加えた。得られる混合物を室温で終夜撹拌した。次いで混合物を真空中で蒸発にかけ、残渣を濃縮塩酸で中和した。次いで混合物を濾過し、フィルターケーキを水で洗浄し、真空乾燥して、２−｛２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］エチル｝−１−エチル−１Ｈ−ベンゾイミダゾール−５−カルボン酸（４５０ｇ、８７．５％）を灰色の固体として得た。

To a solution of methyl 2- {2 [(tert-butoxycarbonyl) amino] ethyl} -1-ethyl-1H-benzimidazole-5-carboxylate (500 g, 1.44 mol) in MeOH (7 L) was added LiOH (51.9 g). , 2.16 mol) in water (3 L) was added. The resulting mixture was stirred at room temperature overnight. The mixture was then evaporated in vacuo and the residue was neutralized with concentrated hydrochloric acid. The mixture is then filtered and the filter cake is washed with water and dried in vacuo to give 2- {2-[(tert-butoxycarbonyl) amino] ethyl} -1-ethyl-1H-benzimidazole-5-carboxylic acid ( 450 g, 87.5%) was obtained as a gray solid.

  Step 4. tert-Butyl (2- {1-ethyl-5-[(2-methoxyethyl) carbamoyl] -1H-benzimidazol-2-yl} ethyl) carbamate

２−｛２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］エチル｝−１−エチル−１Ｈ−ベンゾイミダゾール−５−カルボン酸（３００ｇ、０．９０ｍｏｌ）およびＨＯＢｔ（１７０ｇ、１．２６ｍｏｌ）のＣＨ_２Ｃｌ_２（４Ｌ）混合物に、ＥＤＣ（１７７．７ｇ、１．２６ｍｏｌ）を加えた。得られる混合物を室温で１時間撹拌した。２−メトキシ−エチルアミン（１８９ｇ、２．５２ｍｏｌ）を加え、混合物を室温で３時間撹拌した。ＴＬＣ（酢酸エチル）によって、反応が完了したことが示された。混合物を飽和ＮＨ_４Ｃｌ水溶液（２Ｌ）、ＮａＯＨ水溶液（２Ｌ、０．５ｍｏｌ／Ｌ）、およびブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空中で濃縮して、ｔｅｒｔ−ブチル（２−｛１−エチル−５−［｛（２−メトキシエチル）カルバモイル］−１Ｈ−ベンゾイミダゾール−２−イル｝エチル）カルバメート（２８０ｇ、８０．０％）を白色の固体として得た。

CH ₂ Cl of 2- {2-[(tert-butoxycarbonyl) amino] ethyl} -1-ethyl-1H-benzimidazole-5-carboxylic acid (300 g, 0.90 mol) and HOBt (170 g, 1.26 mol) _{To the} (4L) mixture was added EDC (177.7 g, 1.26 mol). The resulting mixture was stirred at room temperature for 1 hour. 2-Methoxy-ethylamine (189 g, 2.52 mol) was added and the mixture was stirred at room temperature for 3 hours. TLC (ethyl acetate) indicated that the reaction was complete. The mixture was washed with saturated aqueous NH ₄ Cl (2 L), aqueous NaOH (2 L, 0.5 mol / L), and brine, dried over Na ₂ SO ₄ , concentrated in vacuo, and tert-butyl (2- {1-Ethyl-5-[{(2-methoxyethyl) carbamoyl] -1H-benzoimidazol-2-yl} ethyl) carbamate (280 g, 80.0%) was obtained as a white solid.

  Step 5. 2- (2-Aminoethyl) -1-ethyl-N- (2-methoxyethyl) -1H-benzimidazole-5-carboxamide

ｔｅｒｔ−ブチル（２−｛１−エチル−５−［｛（２−メトキシエチル）カルバモイル］−１Ｈ−ベンゾイミダゾール−２−イル｝エチル）カルバメート（１２０ｇ、０．３０８ｍｏｌ）とＭｅＯＨ（１．５Ｌ）の混合物に、塩化水素ガスで飽和させたメタノール（１Ｌ）を滴下した。滴下した後、得られる混合物を室温で３時間撹拌した。次いで混合物を真空中で蒸発にかけ、残渣をＨ_２Ｏ（１Ｌ）に溶解させ、ＣＨ_２Ｃｌ_２（４００ｍＬ×３）で抽出した。水層をＮａＯＨ水溶液（２Ｎ）でｐＨ１１に塩基性化し、ＣＨ_２Ｃｌ_２（２００ｍＬ×３）で抽出した。有機層を合わせて真空中で濃縮して、２−（２−アミノエチル）−１−エチル−Ｎ−（２−メトキシエチル）−１Ｈ−ベンゾイミダゾール−５−カルボキサミド（６０ｇ、６７．２％）を灰色の油状物として得た。MS: 実測値 [M+1] 291.2, 計算値 [M+1] 291.17.

tert-Butyl (2- {1-ethyl-5-[{(2-methoxyethyl) carbamoyl] -1H-benzoimidazol-2-yl} ethyl) carbamate (120 g, 0.308 mol) and MeOH (1.5 L) To the mixture, methanol (1 L) saturated with hydrogen chloride gas was added dropwise. After the addition, the resulting mixture was stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo and the residue was dissolved in H ₂ O (1 L) and extracted with CH ₂ Cl ₂ (400 mL × 3). The aqueous layer was basified to pH 11 with aqueous NaOH (2N) and extracted with CH ₂ Cl ₂ (200 mL × 3). The organic layers were combined and concentrated in vacuo to give 2- (2-aminoethyl) -1-ethyl-N- (2-methoxyethyl) -1H-benzimidazole-5-carboxamide (60 g, 67.2%). Was obtained as a gray oil. MS: Found [M + 1] 291.2, Calculated [M + 1] 291.17.

Preparation Example 17
1- (6-Methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) pyrrolidin-3-amine trihydrochloride Step 1. Preparation of tert-butyl {1- [amino (imino) methyl] pyrrolidin-3-yl} carbamate hydrochloride

ｔｅｒｔ−ブチルピロリジン−２−イルカルバメート（１０ｇ、５３．８ｍｍｏｌ）を含有するジメチルホルムアミド（５０ｍＬ）に、ピラゾールカルボキサミジン（７．６６ｇ、５３．８ｍｍｏｌ）を１回で加えた。次いでジイソプロピルアミン（９．４ｍＬ、５３．８ｍｍｏｌ）を滴下し、反応混合物を室温で終夜撹拌した。ジメチルホルムアミドを蒸発させ、油性残渣に無水ジエチルエーテル（１５０ｍＬ）を加え、微細な白色沈殿が生成するまで撹拌した。沈殿を濾過によって分離して、表題化合物を収率１００％で得た。

To dimethylformamide (50 mL) containing tert-butylpyrrolidin-2-ylcarbamate (10 g, 53.8 mmol) was added pyrazole carboxamidine (7.66 g, 53.8 mmol) in one portion. Diisopropylamine (9.4 mL, 53.8 mmol) was then added dropwise and the reaction mixture was stirred at room temperature overnight. Dimethylformamide was evaporated and anhydrous diethyl ether (150 mL) was added to the oily residue and stirred until a fine white precipitate formed. The precipitate was separated by filtration to give the title compound in 100% yield.

  Step 2. Preparation of 3-[(dimethylamino) methylene] -1-methylpiperidin-4-one

１−メチルピペリジン−４−オン（１０ｇ、８８ｍｍｏｌ）のトルエン（１００ｍＬ）溶液に、１，１−ジメトキシ−Ｎ，Ｎ−ジメチルメタンアミン（５２．７ｇ、０．４４２ｍｏｌ）を加えた。溶液を終夜加熱還流した。真空中で溶媒を蒸発させ、ヘプタン（１００ｍｌ）を加え、再び溶媒を蒸発させて、所望の生成物を得た。ＮＭＲによって、生成物が純度７０〜８０％であることが示され、この生成物をそれ以上精製せずに次のステップで使用した。

1,1-Dimethoxy-N, N-dimethylmethanamine (52.7 g, 0.442 mol) was added to a toluene (100 mL) solution of 1-methylpiperidin-4-one (10 g, 88 mmol). The solution was heated to reflux overnight. The solvent was evaporated in vacuo, heptane (100 ml) was added and the solvent was evaporated again to give the desired product. NMR showed the product to be 70-80% pure and this product was used in the next step without further purification.

  Step 3. Preparation of tert-butyl 1- (6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) pyrrolidin-3-yl] carbamate

３−［（ジメチルアミノ）メチレン］−１−メチルピペリジン−４−オン（４５．４ｇ、０．２７ｍｏｌ）およびｔｅｒｔ−ブチル−１−［アミノ（イミノ）メチル］ピロリジン−３−イル｝カルバメート塩酸塩（６６．１ｇ、０．２５ｍｏｌ）をエタノール（６００ｍＬ）に溶解させ、それにナトリウムメトキシド（１３．５ｇ、０．２５ｍｏｌ）を滴下した。反応混合物を６時間還流させ、次いで室温に冷却した。次いで反応混合物を蒸発乾燥させ、残渣を水（５００ｍＬ）で処理した。沈殿を濾過によって分離し、水（２５０ｍＬ）およびジエチルエーテル（５００ｍＬ）で洗浄し、乾燥させて、表題化合物５９．０ｇ（収率７０．８％）を得た。

3-[(Dimethylamino) methylene] -1-methylpiperidin-4-one (45.4 g, 0.27 mol) and tert-butyl-1- [amino (imino) methyl] pyrrolidin-3-yl} carbamate hydrochloride (66.1 g, 0.25 mol) was dissolved in ethanol (600 mL), and sodium methoxide (13.5 g, 0.25 mol) was added dropwise thereto. The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The reaction mixture was then evaporated to dryness and the residue was treated with water (500 mL). The precipitate was separated by filtration, washed with water (250 mL) and diethyl ether (500 mL), and dried to give 59.0 g (70.8% yield) of the title compound.

  Step 4.1 Preparation of 1- (6-Methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) pyrrolidin-3-amine trihydrochloride

ｔｅｒｔ−ブチル−１−（６−メチル−５，６，７，８−テトラヒドロピリド［４，３−ｄ］ピリミジン−２−イル）ピロリジン−３−イル］カルバメート（５９．０ｇ、０．１７７ｍｏｌ）をメタノール（２００ｍＬ）に溶解させ、０℃に冷却した。これに、４Ｍ塩化水素ジオキサン溶液（５００ｍＬ）を加えた。混合物を室温に温め、室温で１時間撹拌し、次いで蒸発乾燥させた。残渣をエタノール（２００ｍＬ）と共に煮沸し、次いで０℃に冷却し、得られる沈殿を濾別した。これにより表題化合物（５４．９ｇ、収率９０％）が固体として得られた。¹H NMR (DMSO-d₆) δ ppm 2.12 (m, 1H) 2.30 (m, 1H) 2.86-2.94 (s+m, 4H) 3.14-3.24 (m, 1H)
3.37-3.46 (m, 1H) 3.56-3.77 (br m, 6H) 3.78 (br m, 1H) 4.13 (dd, J=14.6, 8.3
Hz, 1H) 4.35 (d, J=14.0 Hz, 1H) 8.28 (s, 1H) 8.52 (br s, 3H) 11.71 (br s,
1H). LRMS [M+H] 234.

tert-Butyl-1- (6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) pyrrolidin-3-yl] carbamate (59.0 g, 0.177 mol) ) Was dissolved in methanol (200 mL) and cooled to 0 ° C. To this was added 4M hydrogen chloride dioxane solution (500 mL). The mixture was warmed to room temperature, stirred at room temperature for 1 hour and then evaporated to dryness. The residue was boiled with ethanol (200 mL), then cooled to 0 ° C. and the resulting precipitate was filtered off. This gave the title compound (54.9 g, 90% yield) as a solid. ¹ H NMR (DMSO-d ₆ ) δ ppm 2.12 (m, 1H) 2.30 (m, 1H) 2.86-2.94 (s + m, 4H) 3.14-3.24 (m, 1H)
3.37-3.46 (m, 1H) 3.56-3.77 (br m, 6H) 3.78 (br m, 1H) 4.13 (dd, J = 14.6, 8.3
Hz, 1H) 4.35 (d, J = 14.0 Hz, 1H) 8.28 (s, 1H) 8.52 (br s, 3H) 11.71 (br s,
1H). LRMS [M + H] 234.

Biological Data h-PGDSTBA fluorescence enzyme assay Prostaglandin D synthase (PGDS) converts substrate prostaglandin _H 2 a (PGH ₂₎ in the prostaglandin _{D 2.} The decrease in PGH _2, was measured through Fe (II) reduction of the remaining PGH ₂ malondialdehyde and (MDA) to 12-HHT. This enzyme assay is carried out to the extent that a fluorescent complex is formed from the non-fluorescent compound MDA and 2-thiobarbituric acid (TBA), substantially as described in US Patent Application Publication US-2004 / 152148 by Lombardt. Based.

Enzyme assay (31 μl) is 100 mM Tris base pH 8.0, 100 μM MgCl ₂ , 0.1 mg / ml IgG rabbit serum, 5.0 μM PGH2 (Cayman, ethanol solution, # 17020), 2.5 mM Contains L-glutathione (Sigma, reduced # G4251), 1: 175,000 human recombinant H-PGDS (from 1 mg / ml), 0.5% DMSO, and inhibitors (various concentrations) It was a thing. 3 μl of diluted inhibitor (dissolved in DMSO) was added to the 384 well assay plate, followed by 25 μl of enzyme solution containing h-PGDS, Tris, MgCl ₂ , IgG, and L-glutathione. After the inhibitor and enzyme solution was preincubated at room temperature for 10 minutes, 3 μl of a solution of the substrate in 10 mM HCl was added to initiate the reaction. After 42 seconds, stop buffer (3 μl) containing FeCl ₂ and citric acid was added to terminate the reaction. After adding 45.5 μl of TBA, the plate was heated in an oven at 70 ° C. for 1 hour. The plate was allowed to cool to room temperature overnight and read the next day with a plate reader at excitation 530 nm and emission 565 nm.

Inhibitor IC ₅₀ was calculated using a 4-parameter fit, using 11 inhibitor concentrations in duplicate in 3-fold serial dilutions. The control of each plate, no inhibitor (effect 0%), and 10 times the inhibitor in excess of the _{IC 50} of (effect 100%) was contained. The highest inhibitor concentration tested was usually 1 μM.

Examples 529, 565, 566, 574-588 and 591 were tested in the following slightly modified assay. Enzyme assay (30 μl during biological process) was 100 mM Trizma pH 8.0, 100 μM MgCl ₂ , 0.1 mg / ml IgG rabbit serum, 5.0 μM PGH2 (Cayman, ethanol solution, # 17020). ), 2.5 mM L-glutathione (Sigma, reduced # G4251), 1: 40,000 human recombinant H-PGDS (from 1 mg / ml), 0.5% DMSO, and inhibitors (various Concentration). After 3 μl of diluted inhibitor (dissolved in DMSO) was added to the 384 well assay plate, 24 μl of enzyme solution containing h-PGDS, Trizma, MgCl ₂ , IgG, and L-glutathione was added. After the inhibitor and enzyme solution was preincubated at room temperature for 10 minutes, 3 μl of a solution of the substrate in 10 mM HCl was added to initiate the reaction. After 40 seconds, 3 μl of stop buffer containing FeCl ₂ and citric acid was added to terminate the reaction. After adding 45 μl of TBA, the plate was heated in a 70 ° C. oven for 1 hour. The plate was allowed to cool to room temperature overnight and read the next day with a plate reader at excitation 530 nm and emission 560 nm. Inhibitor IC ₅₀ was calculated using a four parameter fit using 11 inhibitor concentrations in duplicate at 1/2 log step dilution. Each plate control contained no inhibitor (0% effect) and 500-fold inhibitor (100% effect) over IC ₅₀ . The highest inhibitor concentration tested was usually 10 μM.

The following table shows the IC ₅₀ values thus obtained.

Claims (16)

Compound of formula (I):

Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt [wherein
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, —CN, —NH ₂ , —CH ₃ , —CH ₂ F, —CHF ₂ , —CF ₃ , _-OH, -OCH _3, a -OCH ₂ F, -OCHF 2 or -OCF _3,,
R ⁶ is H, —NH ₂ , —OH, or —CH ₃ ;
R ^6a is H, F, or Cl;
R ⁷ is C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ , said C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ Are: (a) R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , —CONR ^x R ^{b _{, -NR x SO 2 R b,}} -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R b, -OCOOR b , -CONR ^x SO ₂ R ^b, oxo, and -CN may be substituted with 1-3 substituents selected from, optionally substituted with further (b) 1 one or more halo atoms Often,
R ^a is independently from each other C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ^{8 in} each case. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ⁸ are R ^c , —OR, respectively. _{^{d, -S (O) n R}} d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d, -NR x SO 2 R d, - _{^{SO 2 NR x R d, -NR}} x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR d -CONR ^x SO ₂ R ^d, 1~3 substituents selected from oxo and -CN, and may be substituted with one or more halo atoms,
R ^b is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ and Het ⁸ respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 1, Het 5, Het} 6, Het 7, and Het ^{8 each, R} c, _{^{-OR d, -S (O) n}} R d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d, -NR x SO 2 R d _{^{, -SO 2 NR x R d,}} -NR x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR optionally substituted by 1 to 3 substituents selected from ^{d 1} , —CONR ^x SO ₂ R ^d , oxo and —CN, and one or more halo atoms,
n is 0, 1 or 2;
R ^x is, independently in each case, H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl is 1 Optionally substituted with one or more halo atoms,
Aryl ¹ is phenyl or naphthyl;
Het ¹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ¹ is piperidinyl , Not pyrrolidinyl and azetidinyl
Het ² is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ² is a bridged Not a piperidinyl, pyrrolidinyl or azetidinyl ring,
Het ³ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁴ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
Het ⁵ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁶ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁷ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁸ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^c is independently in each case from C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ^12. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² are each selected from R ^e Optionally substituted with 1 to 3 substituents and one or more halo atoms,
R ^d is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 2, Het 9, Het} 10, Het 11, and ^{Het 12} each, from ^{R e} Optionally substituted with 1 to 3 selected substituents and one or more halo atoms,
Aryl ² is phenyl or naphthyl;
Het ⁹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹⁰ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹¹ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ¹² may be (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^{e _{is, -OR x, -S (O)}} n R x, -COR x, -NR x R x, -OCOR x, -COOR x, -NR x COR x, -CONR x R x, -NR x _{^{SO 2 R x, -SO 2 NR}} x R x, -NR x SO 2 NR x NR x, -NR x COOR x, -NR x CONR x R x, -OCONR x R x, -OCOOR x, -CONR x SO ₂ R ^x, is oxo or -CN,
Provided that the compound of formula (I) is
2-hydroxy-N, 6-diphenyl-3-pyridinecarboxamide,
N, 6-diphenyl-3-pyridinecarboxamide,
6- (2-chlorophenyl) -N-phenyl-3-pyridinecarboxamide,
6- (2-fluorophenyl) -N-phenyl-3-pyridinecarboxamide,
6- (2-methylphenyl) -N-phenyl-3-pyridinecarboxamide,
2-methyl-N, 6-diphenyl-3-pyridinecarboxamide,
N- (5-butyl-1,3,4-thiadiazol-2-yl) -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- (4-acetyl-2-thiazolyl) -2-methyl-6-phenyl-3-pyridinecarboxamide,
5-[[(2-methyl-6-phenyl-3-pyridinyl) carbonyl] amino] -2-thiophenecarboxylic acid, methyl ester,
N- [4- (1,1-dimethylethyl) -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- [5-[(acetylamino) methyl] -2-thienyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- [4-[(methylsulfonyl) (methyl) amino] phenyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- [4- (acetylamino) -2-fluorophenyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4-[(2,6-dimethyl-4-morpholinyl) methyl] -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [5- [1- (difluoromethyl) -1H-imidazol-2-yl] -4-methyl-2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [5- (1-ethylpropyl) -1,3,4-thiadiazol-2-yl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -2-methyl-6-phenyl-3-pyridinecarboxamide;
N-antipyridyl-2-methyl-6-phenyl-nicotinamide,
1,2-dihydro-2-oxo-6-phenyl-N-1H-tetrazol-5-yl-3-pyridinecarboxamide,
2-methyl-6-phenyl-N-2-thiazolyl-3-pyridinecarboxamide,
2-methyl-N- (5-methyl-2-thiazolyl) -6-phenyl-3-pyridinecarboxamide,
2-methyl-N- (4-methyl-2-pyridinyl) -6-phenyl-3-pyridinecarboxamide,
N- (5-ethyl-1,3,4-thiadiazol-2-yl) -2-methyl-6-phenyl-3-pyridinecarboxamide;
N- [4- (2-amino-2-oxoethyl) -2-thiazolyl] -2-methyl-6-phenyl-3-pyridinecarboxamide or N- [5- (ethylthio) -1,3,4-thiadiazole -2-yl] -2-methyl-6-phenyl-3-pyridinecarboxamide;
6- (2-methylphenyl) -N- [2-[[[1-phenyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] carbonyl] amino] ethyl] -3-pyridinecarboxamide;
N- [2- (5-methoxy-1H-indol-3-yl) ethyl] -6-phenyl-3-pyridinecarboxamide;
N- [4- [4- [1- (2-Amino-2-oxoethoxy) -5,6,7,8-tetrahydro-2-naphthalenyl] -1-piperidinyl] butyl] -6- (4-chlorophenyl ) -3-pyridinecarboxamide,
N- [4- [4- [1- (2-Amino-2-oxoethoxy) -5,6,7,8-tetrahydro-2-naphthalenyl] -1-piperidinyl] butyl] -6- (4-cyano Phenyl) -3-pyridinecarboxamide,
6- (4-chlorophenyl) -N- [4- [4- (5,6,7,8-tetrahydro-1-methoxy-2-naphthalenyl] -1-piperidinyl] butyl] -3-pyridinecarboxamide;
6- (4-chlorophenyl) -N- [4- [4- (5,6,7,8-tetrahydro-1-methoxy-2-naphthalenyl] -1-piperidinyl] butyl] -3-pyridinecarboxamide;
6- (2-chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -1-[(2,6-difluorophenyl) methyl] -2-oxoethyl] -3-pyridinecarboxamide;
6- (2-Chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -1-[(2,6-difluoro-4-methoxyphenyl) methyl] -2-oxoethyl] -3-pyridine Carboxamide,
6- (2-Chlorophenyl) -N-[(1S) -2-[(4-cyano-1-ethyl-4-piperidinyl) amino] -1-[(2,6-difluorophenyl) methyl] -2- Oxoethyl] -3-pyridinecarboxamide,
6- (2-chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -2-oxo-1- (2-thiazolylmethyl) ethyl] -3-pyridinecarboxamide;
6- (2-Chlorophenyl) -N-[(1S, 3S) -1-[[(4-cyano-1-ethyl-4-piperidinyl) amino] carbonyl] -3-phenyl) butyl] -3-pyridinecarboxamide ,
N-[[6- (2-chlorophenyl) -3-pyridinyl] carbonyl] -2,6-difluoro-L-phenylalanine,
6- (2-chlorophenyl) -N-[(1S) -2-[(cyanomethyl) amino] -1-[(2,6-difluorophenyl) methyl] -2-oxoethyl] -3-pyridinecarboxamide;
6- (2-chlorophenyl) -N-[(1S) -1-[[(cyanomethyl) amino] carbonyl] -3-methylbutyl] -3-pyridinecarboxamide;
6- (4-methoxyphenyl) -N- [2- [4- (1-pyrrolidinylmethyl) phenyl] ethyl] -3-pyridinecarboxamide;
6- (4-fluorophenyl) -N- [2- [4- (1-pyrrolidinylmethyl) phenyl] ethyl] -3-pyridinecarboxamide;
α-[[[[6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxo-3-pyridinyl] carbonyl] amino] -4-hydroxy-benzeneacetic acid,
N- [4- [4- (2,4-dimethoxyphenyl) -1-piperazinyl] butyl] -6-phenyl-3-pyridinecarboxamide;
5-[[2- (4-Fluorophenyl) -1,1-dimethylethylamino] -4-[[[[6- (3-methoxyphenyl) -3-pyridinyl] carbonyl] amino] -5-oxo-pentane acid,
5-[[2- (4-Fluorophenyl) -1,1-dimethylethylamino] -5-oxa-4-[[(6-phenyl) -3-pyridinyl] carbonyl] amino]-(4S) -pentane acid,
5-[(1,1-dimethyl-2-phenylethyl) amino] -5-oxo-4-[[(6-phenyl) -3-pyridinyl] carbonyl] amino] -pentanoic acid,
5-[[2- (4-Chlorophenyl) -1,1-dimethylethyl] amino] -5-oxo-4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid ,
5-oxo-5-[(phenylmethyl) amino] -4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid 1,1-dimethylethyl ester;
5-oxo-5-[(phenylmethyl) amino] -4-[[(6-phenyl-3-pyridinyl) carbonyl] amino] -pentanoic acid,
5-[[(3-Methoxyphenyl) methyl] amino] -5-oxo-4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid 1,1-dimethylethyl ester ,
5-[[(3-methoxyphenyl) methyl] amino] -5-oxo-4-[[(6-phenyl-3-pyridinyl) carbonyl] amino]-(4S) -pentanoic acid,
N- (2-furanylmethyl) -2-methyl-6-phenyl-3-pyridinecarboxamide,
N-methyl-6-phenyl-3-pyridinecarboxamide, or 6- (4-methoxyphenyl) -N-[[3-[(8-methyl-8-azabicyclo [3.2.1] oct-3-yl ) Not phenyl] methyl] -3-pyridinecarboxamide,
Also, when R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each H and R ⁷ is an optionally substituted C ₁ -C ₆ alkyl, R ⁶ is not CH ₃ or OH. ,
R ¹ , R ² , R ⁴ and R ⁵ are each H, R ³ is trifluoromethyl, R ⁶ is CH ₃ , and R ⁷ is methyl or ethyl substituted with ^Ra In certain instances, R ^a is not an optionally substituted phenyl ring or an optionally substituted phenoxy group,
Also an ^{R 1,} R 2, ^{R 4} and ^{R 5} are each H, ^{R 3} is F, and ^{R 6} is H, when ^{R 7} is methyl substituted with ^{R a, R a} Is not an optionally substituted quinolinyl group,
And ^one of R ¹ and R ⁵ is Cl, the other of R ¹ and R ⁵ is H, R ² is H, R ³ is H, R ⁴ is H, R ⁷ is When methyl substituted with -CONR ^x R ^b and R ^b is propyl, R ^b is not substituted with -COHet ³ or -COHet ⁴ ;
The ^{R 6} is ^{H, R 6a} is H, ^{R 7} is, when it is methyl substituted with ^{R a, R a} is not a phenyl group which is substituted,
And when R ⁶ is H and R ^6a is H, R ⁷ is not (CH ₃ ) ₂ CHCH ₂ CH ₂ —. The compound of formula (I) according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, -CH ₃ , -OH or -OCH ₃ or A pharmaceutically acceptable salt or solvate thereof. The formula (I) according to claim 1, wherein R ¹ is H and R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, -CH ₃ , -OH or -OCH _3. Or a pharmaceutically acceptable salt or solvate thereof. R ¹ , R ³ , R ⁴ and R ⁵ are H, R ² is F, or R ¹ , R ³ , R ⁴ and R ⁵ are H, R ² is —CH ₃ , or R ¹ , R ³ , R ⁴ and R ⁵ are H, R ² is —OCH ₃ , or R ¹ , R ² , R ⁴ and R ⁵ are H, R ³ is F, or R ¹ , R ³ and R ⁵ Is H, R ² and R ⁴ are both F, or R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each H, or R ¹ , R ³ and R ⁵ are H, R ² Or R ⁴ is -OCH ₃ , or R ¹ , R ³ and R ⁴ are H, R ² is F, and R ⁵ is -OH or a compound of formula (I) or a pharmacy according to claim 1 Acceptable salts or solvates thereof. R ⁶ is H, the compound or a pharmaceutically acceptable salt or solvate of formula (I) according to any one of claims 1 to 4. ^6. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 5, wherein R <^6a> is H or Cl. R ⁷ is phenyl, —CN, —OH, —NH ₂ , oxo, —COO (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, —COO— (C ₁ -C ₆ alkylene) -NHHet. ⁷ , —NHHet ⁸ , —O— (C ₁ -C ₆ alkylene) -Het ⁸ , —O— (C ₁ -C ₆ alkylene) -phenyl, —CONH ₂ , —CONH— (C ₁ -C ₆ alkylene) -Het ^9, -NH (phenyl), phenyl, -N _(C 1 _{~C 6 alkyl) (C} 1 -C ₆ alkyl), - O _{(phenyl), - NHCOO- (C 1 ~C} 6 alkylene) - phenyl ^{, Het 5, Het 6, Het} 7, and optionally substituted with 1 to 3 substituents selected from Het ⁸ is optionally _C 1 -C ₃ alkyl, wherein the _phenyl, C 3 -C ₈ cycloalkyl ^{Het 5,} Het 6, Het ⁷ and Het ^8, _is, C 1 -C _{6 alkyl,} C 3 -C ₈ cycloalkyl -CO _(C 1 ~C _{6 alkyl),} C 1 _{~C 6} alkoxy, _(C 1 ~ C _{6 alkoxy)} C 1 -C ₆ alkyl, hydroxy _(C 1 -C ₆ alkyl), hydroxyphenyl _(C 1 -C ₆ alkyl), _{halophenyl, (C} 1 -C ₆ alkyl) phenyl, _halo, C 1 -C ₆ haloalkyl, -S _(C 1 -C _{6 alkyl), - SO 2 NH 2,} -COO (C 1 ~C 6 _{alkyl), - SO 2 (C 1} ~C 6 alkyl), phenyl, phenyl _(C 1 ~ C _{6 alkyl), (C} 1 ~C ₆ alkoxyphenyl), _((C 1 ~C ₆ alkoxy) _phenyl) C 1 -C ₆ alkyl, - _(C 1 ~C ₆ alkylene) _-SO 2 (C -C ₆ alkyl), ^{halophenyl, Het 9, Het 10, Het} 11, -COHet 9, - (C 1 ~C 6 _{^{alkylene) -Het 9, - (C 1}} ~C 6 ^{alkylene) -Het} 11, -SO ₂ NH _(C 1 ~C ₆ alkyl), - _(C 1 _{~C 6} alkylene) -COO _(C 1 _{~C 6} alkyl), - OH, and optionally substituted with 1-3 substituents selected from oxo The Het ⁹ , Het ¹⁰ , and Het ¹¹ may be C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy (C ₁ -C _6). A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable substituent, optionally substituted with 1 to 3 substituents selected from alkyl), -OH, and oxo. Forgiveness Salt or solvate thereof as possible. ^{7. The method according} to claim ₁ , wherein R ⁷ is phenyl optionally substituted with 1 to 3 substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and halo. A compound of formula (I) according to one or a pharmaceutically acceptable salt or solvate thereof. R ⁷ is a 5-membered or 6-membered saturated heterocyclic ring containing one O atom or N atom, and the heterocyclic ring is from R ^a , —OR ^b , —COOR ^b , oxo, —NR ^x R ^b 7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 3 selected substituents. R ⁷ is an 8- to 11-membered saturated or partially unsaturated heterocyclic ring containing one oxygen atom, one nitrogen atom, or one oxygen and one nitrogen atom. _ring, C 1 -C ₆ alkyl, -COO _(C 1 ~C _{6 alkyl), - SO 2 (C 1} ~C 6 _{alkyl), - CO (C 1 ~C} 6 ^{alkyl), Het} 7, Het 8, -(C ₁ -C ₆ alkylene) -Het ⁷ , (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, and optionally substituted with 1 to 3 substituents selected from oxo, ⁷ and Het ⁸ _is, C 1 -C ₆ alkyl, hydroxy _(C 1 -C ₆ alkyl), or may be substituted by morpholinylcarbonyl group, according to any one of claims 1 to 6 A compound of formula (I) or pharmaceutically acceptable Rusono salt or solvate thereof. R ⁷ is Het ³ optionally substituted with 1 to 3 substituents R ^a and further optionally substituted with one or more halo atoms. Or a pharmaceutically acceptable salt or solvate thereof.   A pharmaceutical composition comprising a compound of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A method of treating an allergic or respiratory condition in a subject in need thereof, wherein the subject comprises a therapeutically effective amount of a compound of formula (I):

Or a method comprising administering a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, wherein
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, —CN, —NH ₂ , —CH ₃ , —CH ₂ F, —CHF ₂ , —CF ₃ , _-OH, -OCH _3, a -OCH ₂ F, -OCHF 2 or -OCF _3,,
R ⁶ is H, —NH ₂ , —OH, or —CH ₃ ;
R ^6a is H, F, or Cl;
R ⁷ is C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ , said C ₁ -C ₆ alkyl, phenyl, Het ¹ , Het ² , Het ³ , or Het ⁴ Are: (a) R ^a , —OR ^b , —S (O) _n R ^b , —COR ^b , —NR ^x R ^b , —OCOR ^b , —COOR ^b , —NR ^x COR ^b , —CONR ^x R ^{b _{, -NR x SO 2 R b,}} -SO 2 NR x R b, -NR x SO 2 NR x R b, -NR x COOR b, -NR x CONR x R b, -OCONR x R b, -OCOOR b , -CONR ^x SO ₂ R ^b, oxo, and -CN may be substituted with 1-3 substituents selected from, optionally substituted with further (b) 1 one or more halo atoms Often,
R ^a is independently from each other C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ^{8 in} each case. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ , and Het ⁸ are R ^c , —OR, respectively. _{^{d, -S (O) n R}} d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d, -NR x SO 2 R d, - _{^{SO 2 NR x R d, -NR}} x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR d -CONR ^x SO ₂ R ^d, 1~3 substituents selected from oxo and -CN, and may be substituted with one or more halo atoms,
R ^b is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ¹ , Het ⁵ , Het ⁶ , Het ⁷ and Het ⁸ respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 1, Het 5, Het} 6, Het 7, and Het ^{8 each, R} c, _{^{-OR d, -S (O) n}} R d, -COR d, -NR x R d, -OCOR d, -COOR d, -NR x COR d, -CONR x R d, -NR x SO 2 R d _{^{, -SO 2 NR x R d,}} -NR x SO 2 NR x R d, -NR x COOR d, -NR x CONR x R d, -OCONR x R d, -OCOOR optionally substituted by 1 to 3 substituents selected from ^{d 1} , —CONR ^x SO ₂ R ^d , oxo and —CN, and one or more halo atoms,
n is 0, 1 or 2;
R ^x is, independently in each case, H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl is 1 Optionally substituted with one or more halo atoms,
Aryl ¹ is phenyl or naphthyl;
Het ¹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ¹ is piperidinyl , Not pyrrolidinyl and azetidinyl
Het ² is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N, provided that Het ² is a bridged Not a piperidinyl, pyrrolidinyl or azetidinyl ring,
Het ³ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁴ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
Het ⁵ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁶ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ⁷ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ⁸ is (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^c is independently in each case from C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ^12. Said C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² are each selected from R ^e Optionally substituted with 1 to 3 substituents and one or more halo atoms,
R ^d is in each case from H, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ bicycloalkyl, Aryl ² , Het ⁹ , Het ¹⁰ , Het ¹¹ , and Het ¹² respectively. are independently selected, said _C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 6 _{-C 12} ^{bicycloalkyl, Aryl 2, Het 9, Het} 10, Het 11, and ^{Het 12} each, from ^{R e} Optionally substituted with 1 to 3 selected substituents and one or more halo atoms,
Aryl ² is phenyl or naphthyl;
Het ⁹ is a 3-8 membered saturated or partially unsaturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹⁰ is a 6-12 membered saturated or partially unsaturated polycyclic heterocycle containing 1 or 2 heteroatoms selected from O and N;
Het ¹¹ is (i) a 6-membered aromatic heterocycle containing 1 to 3 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O or S atom And a 5-membered aromatic heterocycle containing 0 to 3 N atoms,
Het ¹² may be (i) a 10-membered bicyclic aromatic heterocycle containing 1 to 4 N atoms, or (ii) (a) 1 to 4 N atoms or (b) 1 O Or a 9-membered bicyclic aromatic heterocycle containing S atoms and 0-3 N atoms,
R ^{e _{is, -OR x, -S (O)}} n R x, -COR x, -NR x R x, -OCOR x, -COOR x, -NR x COR x, -CONR x R x, -NR x _{^{SO 2 R x, -SO 2 NR}} x R x, -NR x SO 2 NR x NR x, -NR x COOR x, -NR x CONR x R x, -OCONR x R x, -OCOOR x, -CONR x SO ₂ R ^x, oxo or -CN].   14. The method of claim 13, wherein the disease or condition is asthma.   Use of a compound according to claim 13 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating an allergic condition or a respiratory condition.   A combination of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or solvate thereof and a second pharmacologically active compound.